A combination therapy of an insulin sensitizer and an FBPase inhibitor is disclosed for the treatment of diabetes, and other diseases where the control of blood glucose levels or an improvement in insulin sensitivity, reduction in insulin levels or an enhancement of insulin secretion is beneficial. Compositions used in the therapy are also disclosed.
Diabetes mellitus (or diabetes) is one of the most prevalent diseases in the world today. Diabetes patients have been divided into two classes, namely type I or insulin-dependent diabetes mellitus and type II or non-insulin dependent diabetes mellitus (NIDDM). NIDDM accounts for approximately 90% of all diabetics and is estimated to affect 12-14 million adults in the U.S. alone (6.6% of the population). NIDDM is characterized by both fasting hyperglycemia and exaggerated postprandial increases in plasma glucose levels. NIDDM is associated with a variety of long-term complications, including microvascular diseases such as retinopathy, nephropathy and neuropathy, and macrovascular diseases such as coronary heart disease. Numerous studies in animal models demonstrate a causal relationship between long term hyperglycemia and complications. Results from the Diabetes Control and Complications Trial (DCCT) and the Stockholm Prospective Study demonstrate this relationship for the first time in man by showing that insulin-dependent diabetics with tighter glycemic control are at substantially lower risk for the development and progression of these complications. Tighter control is also expected to benefit NIDDM patients.
Current therapies used to treat NIDDM patients entail both controlling lifestyle risk factors and pharmaceutical intervention. First-line therapy for NIDDM is typically a tightly-controlled regimen of diet and exercise since an overwhelming number of NIDDM patients are overweight or obese (67%) and since weight loss can improve insulin secretion, insulin sensitivity and lead to normoglycemia. Normalization of blood glucose occurs in less than 30% of these patients due to poor compliance and poor response. Patients with hyperglycemia not controlled by diet alone are subsequently treated with oral hypoglycemics or insulin. Until recently, the sulfonylureas were the only class of oral hypoglycemic agents available for NIDDM. Treatment with sulfonylureas leads to effective blood glucose lowering in only 70% of patients and only 40% after 10 years of therapy. Patients that fail to respond to diet and sulfonylureas are subsequently treated with daily insulin injections to gain adequate glycemic control.
Although the sulfonylureas represent a major therapy for NIDDM patients, four factors limit their overall success. First, as mentioned above, a large segment of the NIDDM population do not respond adequately to sulfonylurea therapy (i.e. primary failures) or become resistant (i.e. secondary failures). This is particularly true in NIDDM patients with advanced NIDDM since these patients have severely impaired insulin secretion. Second, sulfonylurea therapy is associated with an increased risk of severe hypoglycemic episodes. Third, chronic hyperinsulinemia has been associated with increased cardiovascular disease although this relationship is considered controversial and unproven. Last, sulfonylureas are associated with weight gain, which leads to worsening of peripheral insulin sensitivity and thereby can accelerate the progression of the disease.
Results from the U.K. Diabetes Prospective Study also showed that patients undergoing maximal therapy of a sulfonylurea, metformin, or a combination of the two, were unable to maintain normal fasting glycemia over the six year period of the study.
U.K. Prospective Diabetes Study 16. Diabetes, 44:1249-158 (1995). These results further illustrate the great need for alternative therapies.
Another drug therapy recently developed for NIDDM patients acts on the underlying mechanisms of insulin resistance and thereby lower glucose by enhancing insulin action at both peripheral and hepatic sites. Saltiel and Olefsky Diabetes 45: 1661-1669 (1996). Accordingly, these agents are reported to increase insulin-dependent glucose disposal and to inhibit HGO. These agents are commonly referred to as xe2x80x9cinsulin sensitizersxe2x80x9d.
One class of insulin sensitizers are compounds containing a thiazolidinedione. These compounds are reported to enhance insulin action without directly stimulating insulin secretion. Thiazolidinediones markedly decrease glucose levels in a variety of obese, insulin-resistant diabetic animal models including the KK-mouse, ob/ob mouse, Zucker Diabetic Fatty rat and db/db mouse. Similar effects are found in non-genetic diabetic animal models, including the fructose fed rat and high fat fed rat. Animal models characterized by severe hypoinsulinemia, e.g. the STZ rat, fail to respond to these agents unless treated with insulin. Thiazolidinediones are also reported to restore the ability of insulin to suppress HGO.
Although the molecular target of insulin sensitizers and more specifically thiazolidinedione analogs is unknown, several studies suggest that peroxisome proliferator-activated receptors (PPAR xcex3s) may be the target and therefore that ligands to these receptors will be useful antihyperglycemic agents. Lehmann et al. J. Biol. Chem. 270: 12953-12956 (1995). PPAR xcex3s are members of the steroid/thyroid hormone receptor superfamily of transcription factors. At least three PPAR xcex3s exist, namely the xcex1, xcex2 and xcex3 receptors and thiazolidinediones have been identified as ligands that activate the xcex2 and xcex3 receptors. Binding occurs at a concentration achieved in vivo and some data suggests that there is a correlation between PPAR xcex3 binding affinity and in vivo activity. Wilson et al. J. Med. Chem. 39: 665-668 (1996).
PPAR xcex3s exist as a heterodimer with the retinoic acid X receptor (RXR). A co-repressor protein has been postulated to maintain the receptor in an inactive state similar to other nuclear receptors. Binding of molecules to the complex, i.e. PPAR xcex3 ligands and/or RXR ligands may lead to dissociation of the co-repressor protein and activation of the receptor, which in turn is postulated to interact with specific DNA sequences, PPRE""s, and to activate or repress gene transcription. Accordingly, RXR ligands are thought to enhance insulin sensitivity and therefore be useful as antidiabetics either alone or in combination with PPAR xcex3 agonists such as a thiazolidinedione. Heyman et al., WO 97/10819. In db/db mice, the combination of an RXR ligand and a PPAR xcex3 agonist reduces glucose levels more than either component alone.
Other classes of insulin sensitizers (i.e. non-thiazolidinediones) have been identified. For example, the insulin sensitizers SB 236636 and SB 219994 are 3-aryl-2-alkoxy propanoic acids. These compounds are reported to bind to human PPAR xcex3 with high affinity. SB 236636 is equipotent with thiazolidinedione BRL 49653 in stimulation of glucose transport in differentiated 3T3-L1 adipocytes and in glucose lowering activity in ob/ob mice. Young et al. Diabetes (1997). Relative to other thiazolidinediones, SB 236636 was shown to bind with higher affinity to crude extracts of Sf9 cells transfected with full length hPPAR xcex3 and rat adipocytes. This higher binding affinity correlated well with in vivo potency.
Some data suggests that chronic activation of PKC isoenzymes is involved in the generation of muscle insulin resistance and that insulin sensitizers may decrease the translocation of PKC isoenzymes from the cytosolic to particulate fractions in red skeletal muscle and therefore PKC activation. Schmitz-Peiffer et al. Am. J. Physiol. 273: E915-E921 (1997)
Angiotensin II antagonists and angiotensin converting enzyme inhibitors may be useful in enhancing insulin sensitivity based on potential interactions between angiotensin II and insulin signaling systems. Torlone et al. Diabetes Care 16: 1347-1355 (1993); Howard G. et al., Circulation 93: 1809-1817 (1996); Folli et al. J. Clin. Invest. 100: 2158-2169 (1997); Tamura et al., WO9737688 A2.
Thus, there are several mechanisms by which agents may act as insulin sensitizers.
Gluconeogenesis from pyruvate is a highly regulated biosynthetic pathway requiring eleven enzymes. Seven enzymes catalyze reversible reactions and are common to both gluconeogenesis and glycolysis. Four enzymes catalyze reactions unique to gluconeogenesis, namely pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase and glucose-6-phosphatase. Overall flux through the pathway is controlled by the specific activities of these enzymes, the enzymes that catalyzed the corresponding steps in the glycolytic direction, and by substrate availability. Dietary factors (glucose, fat) and hormones (insulin, glucagon, glucocorticoids, epinephrine) coordinatively regulate enzyme activities in the gluconeogenesis and glycolysis pathways through gene expression and post-translational mechanisms.
Synthetic inhibitors of fructose-1,6-bisphosphatase (hereinafter xe2x80x9cFBPasexe2x80x9d) have been reported. McNiel reported that fructose-2,6-bisphosphate analogs inhibit FBPase by binding to the substrate site. J. Am. Chem. Soc., 106:7851-7853 (1984); U.S. Pat. No. 4,968,790 (1984). These compounds, however, were relatively weak and did not inhibit glucose production in hepatocytes presumably due to poor cell penetration.
Gruber reported that some nucleosides can lower blood glucose in the whole animal through inhibition of FBPase. These compounds exert their activity by first undergoing phosphorylation to the corresponding monophosphate. EP 0 427 799 B 1.
Gruber et al. U.S. Pat. No. 5,658,889 described the use of inhibitors of the AMP site of FBPase to treat diabetes. WO 98/39344, WO 98/39343, and WO 98/39342 describe the use of FBPase inhibitors to treat diabetes.
The instant invention is a combination therapy and a composition for the treatment for diabetes and diseases responding to improved glycemic control or to improve peripheral insulin sensitivity. The therapy requires administration of a insulin sensitizer agent, e.g. PPAR xcex3 agonist, RXR ligand, or another agent known to enhance insulin action and an FBPase inhibitor either together or at a different time such that improved glycemic control is achieved. In another aspect of the invention, the combined therapy results in decreases in hepatic glucose output beyond that observed for glucose lowering doses of the insulin sensitizer agent. Furthermore, the combined therapy can result in improvements in insulin resistance and/or insulin secretion beyond that observed for either agent alone. Yet another aspect of the invention is that a combination therapy achieves similar benefits as observed with one or the other therapies alone but at significantly lower doses.
The present invention relates to methods and compositions for treating an animal having NIDDM or a condition associated with insulin resistance by administering to the animal a composition containing a pharmaceutically effective amount of an agent that enhances insulin sensitivity and a pharmaceutically effective amount of an FBPase inhibitor. The compositions of this invention are adapted to cure, improve or prevent one or more symptoms of NIDDM. A preferred drug combination will have high potency and low toxicity.
Another object of the invention relates to methods and compositions for treating insulin-requiring NIDDM patients. The combination therapy decreases the insulin requirement and associated safety risks.
Another object of the invention relates to methods and compositions for treating diseases or conditions characterized by insulin resistance, including obesity, hypertension, impaired glucose tolerance, and polycystic ovarian syndrome. Individuals with syndrome X, renal disease, or pancreatitis are also effectively treated with the combination therapy.
Another object of the invention is the use of insulin sensitizer to attenuate certain potentially adverse effects that could be associated with FBPase inhibitor therapy such as lactate and triglyceride elevation.
Another object of the invention is the use of FBPase inhibitors to attenuate certain potentially adverse effects that could be associated with insulin sensitizers such as weight gain.
Another aspect of the invention is to use FBPase inhibitors in combination with insulin sensitizer therapies that include administration of agents that enhance endogenous or exogenous insulin levels, such as sulfonylureas, insulin, or insulin mimetics.
Definitions
In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise.
X and X3 group nomenclature as used herein in formulae I and X describes the group attached to the phosphonate and ends with the group attached to the heteroaromatic ring. For example, when X is alkylamino, the following structure is intended:
(heteroaromatic ring)-NR-alk-P(O)(OR1)2
Likewise, A, B, C, D, E, Axe2x80x3, Bxe2x80x3, Cxe2x80x3, Dxe2x80x3, Exe2x80x3, A2, L2, E2, and J2 groups and other substituents of the heteroaromatic ring are described in such a way that the term ends with the group attached to the heteroaromatic ring. Generally, substituents are named such that the term ends with the group at the point of attachment.
The term xe2x80x9carylxe2x80x9d refers to aromatic groups which have 5-14 ring atoms and at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted. Suitable aryl groups include phenyl and furan-2,5-diyl.
Carbocyclic aryl groups are groups wherein the ring atoms on the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and polycyclic or fused compounds such as optionally substituted naphthyl groups.
Heterocyclic aryl or heteroaryl groups are groups having from 1 to 4 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include oxygen, sulfur, nitrogen, and selendum. Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, and the like, all optionally substituted.
The term xe2x80x9cannulationxe2x80x9d or xe2x80x9cannulatedxe2x80x9d refers to the formation of an additional cyclic moiety onto an existing aryl or heteroaryl group. The newly formed ring may be carbocyclic or heterocyclic, saturated or unsaturated, and contains 2-9 new atoms of which 0-3 may be heteroatoms taken from the group of N, O, and S. The annulation may incorporate atoms from the X group as part of the newly formed ring. For example, the phrase xe2x80x9ctogether L2 and E2 form an annulated cyclic group,xe2x80x9d includes 
The term xe2x80x9cbiarylxe2x80x9d represents aryl groups containing more than one aromatic ring including both fused ring systems and aryl groups substituted with other aryl groups. Such groups may be optionally substituted. Suitable biaryl groups include naphthyl and biphenyl.
The term xe2x80x9calicyclicxe2x80x9d means compounds which combine the properties of aliphatic and cyclic compounds. Such cyclic compounds include but are not limited to, aromatic, cycloalkyl and bridged cycloalkyl compounds. The cyclic compound includes heterocycles. Cyclohexenylethyl and cyclohexylethyl are suitable alicyclic groups. Such groups may be optionally substituted.
The term xe2x80x9coptionally substitutedxe2x80x9d or xe2x80x9csubstitutedxe2x80x9d includes groups substituted by one to four substituents, independently selected from lower alkyl, lower aryl, lower aralkyl, lower alicyclic, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, amino, guanidino, amidino, halo, lower alkylthio, oxo, acylalkyl, carboxy esters, carboxyl, -carboxamido, nitro, acyloxy, aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl, arylamino, aralkylamino, phosphono, sulfonyl, -carboxamidoalkylaryl, -carboxamidoaryl, hydroxyalkyl, haloalkyl, alkylarninoalkylcarboxy-, aminocarboxamidoalkyl-, cyano, lower alkoxyalkyl, lower perhaloalkyl, and arylalkyloxyalkyl. xe2x80x9cSubstituted arylxe2x80x9d and xe2x80x9csubstituted heteroarylxe2x80x9d preferably refers to aryl and heteroaryl groups substituted with 1-3 substituents. Preferably these substituents are selected from the group consisting of lower alkyl, lower alkoxy, lower perhaloalkyl, halo, hydroxy, and amino. xe2x80x9cSubstitutedxe2x80x9d when describing an R5 group does not include annulation.
The term xe2x80x9caralkylxe2x80x9d refers to an alkyl group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl, and the like, and may be optionally substituted. The term xe2x80x9c-aralkyl-xe2x80x9d refers to a divalent group -aryl-alkylene-. xe2x80x9cHeteroarylalkylxe2x80x9d refers to an alkylene group substituted with a heteroaryl group.
The term xe2x80x9c-alkylaryl-xe2x80x9d refers to the group -alk-aryl- where xe2x80x9calkxe2x80x9d is an alkylene group. xe2x80x9cLower -alkylaryl-xe2x80x9d refers to such groups where alkylene is lower alkylene.
The term xe2x80x9clowerxe2x80x9d referred to herein in connection with organic radicals or compounds respectively defines such as with up to and including 10, preferably up to and including 6, and advantageously one to four carbon atoms. Such groups may be straight chain, branched, or cyclic.
The terms xe2x80x9carylaminoxe2x80x9d (a), and xe2x80x9caralkylaminoxe2x80x9d (b), respectively, refer to the group xe2x80x94NRRxe2x80x2 wherein respectively, (a) R is aryl and. Rxe2x80x2 is hydrogen, alkyl, aralkyl or aryl, and (b) R is aralkyl and Rxe2x80x2 is hydrogen or aralkyl, aryl, alkyl.
The term xe2x80x9cacylxe2x80x9d refers to xe2x80x94C(O)R where R is alkyl and aryl.
The term xe2x80x9ccarboxy estersxe2x80x9d refers to xe2x80x94C(O)OR where R is alkyl, aryl, aralkyl, and alicyclic, all optionally substituted.
The term xe2x80x9ccarboxylxe2x80x9d refers to xe2x80x94C(O)OH.
The term xe2x80x9coxoxe2x80x9d refers to xe2x95x90O in an alkyl group.
The term xe2x80x9caminoxe2x80x9d refers to xe2x80x94NRRxe2x80x2 where R and Rxe2x80x2 are independently selected from hydrogen, alkyl, aryl, aralkyl and alicyclic, all except H are optionally substituted; and R and R1 can form a cyclic ring system.
The term xe2x80x9ccarbonylaminoxe2x80x9d and xe2x80x9c-carbonylamino-xe2x80x9d refers to RCONRxe2x80x94 and xe2x80x94CONRxe2x80x94, respectively, where each R is independently hydrogen or alkyl.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d refers to xe2x80x94F, xe2x80x94Cl, xe2x80x94Br and xe2x80x94I.
The term xe2x80x9c-oxyalkylamino-xe2x80x9d refers to xe2x80x94O-alk-NRxe2x80x94, where xe2x80x9calkxe2x80x9d is an alkylene group and R is H or alkyl.
The term xe2x80x9c-alkylaminoalkylcarboxy-xe2x80x9d refers to the group -alk-NR-alk-C(O)xe2x80x94Oxe2x80x94 where xe2x80x9calkxe2x80x9d is an alkylene group, and R is a H or lower alkyl.
The term xe2x80x9c-alkylaminocarbonyl-xe2x80x9d refers to the group -alk-NRxe2x80x94C(O)xe2x80x94 where xe2x80x9calkxe2x80x9d is an alkylene group, and R is a H or lower alkyl.
The term xe2x80x9c-oxyalkyl-xe2x80x9d refers to the group xe2x80x94O-alk- where xe2x80x9calkxe2x80x9d is an alkylene group.
The term xe2x80x9c-alkylcarboxyalkyl-xe2x80x9d refers to the group -alk-C(O)xe2x80x94O-alk- where each alk is independently an alkylene group.
The term xe2x80x9calkylxe2x80x9d refers to saturated aliphatic groups including straight-chain, branched chain and cyclic groups. Alkyl groups may be optionally substituted. Suitable alkyl groups include methyl, isopropyl, and cyclopropyl.
The term xe2x80x9ccyclic alkylxe2x80x9d or xe2x80x9ccycloalkylxe2x80x9d refers to alkyl groups that are cyclic. Suitable cyclic groups include norbornyl and cyclopropyl. Such groups may be substituted.
The term xe2x80x9cheterocyclicxe2x80x9d and xe2x80x9cheterocyclic alkylxe2x80x9d refer to cyclic groups of 3 to 10 atoms, more preferably 3 to 6 atoms, containing at least one heteroatom, preferably 1 to 3 heteroatoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. Heterocyclic groups may be attached through a nitrogen or through a carbon atom in the ring. Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl, and pyridyl.
The term xe2x80x9cphosphonoxe2x80x9d refers to xe2x80x94PO3R2, where R is selected from the group consisting of xe2x80x94H, alkyl, aryl, aralkyl, and alicyclic.
The term xe2x80x9csulphonylxe2x80x9d or xe2x80x9csulfonylxe2x80x9d refers to xe2x80x94SO3R, where R is H, alkyl, aryl, aralkyl, and alicyclic.
The term xe2x80x9calkenylxe2x80x9d refers to unsaturated groups which contain at least one carbon-carbon double bond and includes straight-chain, branched-chain and cyclic groups. Alkenyl groups may be optionally substituted. Suitable alkenyl groups include allyl. xe2x80x9c1-alkenylxe2x80x9d refers to alkenyl groups where the double bond is between the first and second carbon atom. If the 1-alkenyl group is attached to another group, e.g. it is a W substituent attached to the cyclic phosph(oramid)ate, it is attached at the first carbon.
The term xe2x80x9calkynylxe2x80x9d refers to unsaturated groups which contain at least one carbon-carbon triple bond and includes straight-chain, branched-chain and cyclic groups. Alkynyl groups may be optionally substituted. Suitable alkynyl groups include ethynyl. xe2x80x9c1-alkynylxe2x80x9d refers to alkynyl groups where the triple bond is between the first and second carbon atom. If the 1-alkynyl group is attached to another group, e.g. it is a W substituent attached to the cyclic phosph(oramid)ate, it is attached at the first carbon.
The term xe2x80x9calkylenexe2x80x9d refers to a divalent straight chain, branched chain or cyclic saturated aliphatic group.
The term xe2x80x9c-cycloalkylene-COOR3xe2x80x9d refers to a divalent cyclic alkyl group or heterocyclic group containing 4 to 6 atoms in the ring, with 0-1 heteroatoms selected from O, N, and S. The cyclic alkyl or heterocyclic group is substituted with xe2x80x94COOR3.
The term xe2x80x9cacyloxyxe2x80x9d refers to the ester group xe2x80x94Oxe2x80x94C(O)R, where R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or alicyclic.
The term xe2x80x9caminoalkyl-xe2x80x9d refers to the group NR2-alk- wherein xe2x80x9calkxe2x80x9d is an alkylene group and R is selected from H, alkyl, aryl, aralkyl, and alicyclic.
The term xe2x80x9c-alkyl(hydroxy)-xe2x80x9d refers to an xe2x80x94OH off the alkyl chain. When this term is an X group, the xe2x80x94OH is at the position a to the phosphorus atom.
The term xe2x80x9calkylaminoalkyl-xe2x80x9d refers to the group alkyl-NR-alk- wherein each xe2x80x9calkxe2x80x9d is an independently selected alkylene, and R is H or lower alkyl. xe2x80x9cLower alkylaminoalkyl-xe2x80x9d refers to groups where each alkylene group is lower alkylene.
The term xe2x80x9carylaminoalkyl-xe2x80x9d refers to the group aryl-NR-alk- wherein xe2x80x9calkxe2x80x9d is an alkylene group and R is H, alkyl, aryl, aralkyl, and alicyclic. In xe2x80x9clower arylaminoalkyl-xe2x80x9d, the alkylene group is lower alkylene.
The term xe2x80x9calkylaminoaryl-xe2x80x9d refers to the group alkyl-NR-aryl- wherein xe2x80x9carylxe2x80x9d is a divalent group and R is H, alkyl, aralkyl, and alicyclic. In xe2x80x9clower alkylaminoaryl-xe2x80x9d, the alkylene group is lower alkyl.
The term xe2x80x9calkyloxyaryl-xe2x80x9d refers to an aryl group substituted with an alkyloxy group. In xe2x80x9clower alkyloxyaryl-xe2x80x9d, the alkyl group is lower alkyl.
The term xe2x80x9caryloxyalkyl-xe2x80x9d refers to an alkyl group substituted with an aryloxy group.
The term xe2x80x9caralkyloxyalkyl-xe2x80x9d refers to the group aryl-alk-O-alk- wherein xe2x80x9calkxe2x80x9d is an alkylene group. xe2x80x9cLower aralkyloxyalkyl-xe2x80x9d refers to such groups where the alkylene groups are lower alkylene.
The term xe2x80x9c-alkoxy-xe2x80x9d or xe2x80x9c-alkyloxy-xe2x80x9d refers to the group -alk-Oxe2x80x94 wherein xe2x80x9calkxe2x80x9d is an alkylene group. The term xe2x80x9calkoxy-xe2x80x9d refers to the group alkyl-Oxe2x80x94.
The term xe2x80x9c-alkoxyalkyl-xe2x80x9d or xe2x80x9c-alkyloxyalkyl-xe2x80x9d refer to the group -alk-O-alk- wherein each xe2x80x9calkxe2x80x9d is an independently selected alkylene group. In xe2x80x9clower -alkoxyalkyl-xe2x80x9d, each alkylene is lower alkylene.
The terms xe2x80x9calkylthio-xe2x80x9d and xe2x80x9c-alkylthio-xe2x80x9d refer to the groups alkyl-Sxe2x80x94, and -alk-Sxe2x80x94, respectively, wherein xe2x80x9calkxe2x80x9d is alkylene group.
The term xe2x80x9c-alkylthioalkyl-xe2x80x9d refers to the group -alk-S-alk- wherein each xe2x80x9calkxe2x80x9d is an independently selected alkylene group. In xe2x80x9clower -alkylthioalkyl-xe2x80x9d each alkylene is lower alkylene.
The term xe2x80x9calkoxycarbonyloxy-xe2x80x9d refers to alkyl-Oxe2x80x94C(O)xe2x80x94Oxe2x80x94.
The term xe2x80x9caryloxycarbonyloxy-xe2x80x9d refers to aryl-Oxe2x80x94C(O)xe2x80x94Oxe2x80x94.
The term xe2x80x9calkylthiocarbonyloxy-xe2x80x9d refers to alkyl-Sxe2x80x94C(O)xe2x80x94Oxe2x80x94.
The term xe2x80x9c-alkoxycarbonylamino-xe2x80x9d refers to -alk-Oxe2x80x94C(O)xe2x80x94NR1xe2x80x94, where xe2x80x9calkxe2x80x9d is alkylene and R1 includes xe2x80x94H, alkyl, aryl, alicyclic, and aralkyl.
The term xe2x80x9c-alkylaminocarbonylamino-xe2x80x9d refers to -alk-NR1xe2x80x94C(O)xe2x80x94NR1xe2x80x94, where xe2x80x9calkxe2x80x9d is alkylene and R1 is independently selected from H, alkyl, aryl, aralkyl, and alicyclic.
The terms xe2x80x9camidoxe2x80x9d or xe2x80x9ccarboxamidoxe2x80x9d refer to NR2xe2x80x94C(O)xe2x80x94 and RC(O)xe2x80x94NR1xe2x80x94, where R and R1 include H, alkyl, aryl, aralkyl, and alicyclic. The term does not include urea, xe2x80x94NRxe2x80x94C(O)xe2x80x94NRxe2x80x94.
The terms xe2x80x9ccarboxamidoalkylarylxe2x80x9d and xe2x80x9ccarboxamidoarylxe2x80x9d refers to an aryl-alk-NR1xe2x80x94C(O)xe2x80x94, and an xe2x80x94NR1xe2x80x94C(O)-alk-, respectively, where xe2x80x9carxe2x80x9d is aryl, and xe2x80x9calkxe2x80x9d is alkylene, R1 and R include H, alkyl, aryl, aralkyl, and aliyclic.
The term xe2x80x9c-alkylcarboxamido-xe2x80x9d or xe2x80x9c-alkylcarbonylamino-xe2x80x9d refers to the group -alk-C(O)N(R)xe2x80x94 wherein xe2x80x9calkxe2x80x9d is an alkylene group and R is H or lower alkyl.
The term xe2x80x9c-alkylaminocarbonyl-xe2x80x9d refers to the group -alk-NRxe2x80x94C(O)xe2x80x94 wherein xe2x80x9calkxe2x80x9d is an alkylene group and R is H or lower alkyl.
The term xe2x80x9caminocarboxamidoalkyl-xe2x80x9d refers to the group NR2xe2x80x94C(O)xe2x80x94N(R)-alk- wherein R is an alkyl group or H and xe2x80x9calkxe2x80x9d is an alkylene group. xe2x80x9cLower aminocarboxamidoalkyl-xe2x80x9d refers to such groups wherein xe2x80x9calkxe2x80x9d is lower alkylene.
The term xe2x80x9cthiocarbonatexe2x80x9d refers to xe2x80x94Oxe2x80x94C(S)xe2x80x94Oxe2x80x94 either in a chain or in a cyclic group.
The term xe2x80x9chydroxyalkylxe2x80x9d refers to an alkyl group substituted with one xe2x80x94OH.
The term xe2x80x9chaloalkylxe2x80x9d refers to an alkyl group substituted with one halo, selected from the group I, Cl, Br, F.
The term xe2x80x9ccyanoxe2x80x9d refers to xe2x80x94Cxe2x89xa1N.
The term xe2x80x9cnitroxe2x80x9d refers to xe2x80x94NO2.
The term xe2x80x9cacylalkylxe2x80x9d refers to an alkyl-C(O)-alk-, where xe2x80x9calkxe2x80x9d is alkylene.
The term xe2x80x9cheteroarylalkylxe2x80x9d refers to an alkyl group substituted with a heteroaryl group.
The term xe2x80x9c-1,1-dihaloalkyl-xe2x80x9d refers to an X group where the 1 position and therefore halogens are xcex1 to the phosphorus atom.
The term xe2x80x9cperhaloxe2x80x9d refers to groups wherein every Cxe2x80x94H bond has been replaced with a C-halo bond on an aliphatic or aryl group. Suitable perhaloalkyl groups include xe2x80x94CF3 and xe2x80x94CFCl2.
The term xe2x80x9cguanidinoxe2x80x9d refers to both xe2x80x94NRxe2x80x94C(NR)xe2x80x94NR2 as well as xe2x80x94Nxe2x95x90C(NR2)2 where each R group is independently selected from the group of xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, and alicyclic, all except xe2x80x94H are optionally substituted.
The term xe2x80x9camidinoxe2x80x9d refers to xe2x80x94C(NR)xe2x80x94NR2 where each R group is independently selected from the group of xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, and alicyclic, all except xe2x80x94H are optionally substituted.
The term xe2x80x9c2-thiazolyl-xe2x80x9d or xe2x80x9c2-oxazolyl-xe2x80x9d or xe2x80x9c2-selenozolyxe2x80x9d refers to the corresponding base and its attachment of the X group at the 2-position of the heterocycle.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d includes salts of compounds of formula I and its prodrugs derived from the combination of a compound of this invention and an organic or inorganic acid or base. Suitable acids include HCl.
The term xe2x80x9cprodrugxe2x80x9d as used herein refers to any compound that when administered to a biological system generates the xe2x80x9cdrugxe2x80x9d substance (a biologically active compound) as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s). Standard prodrugs are formed using groups attached to functionality, e.g. HOxe2x80x94, HSxe2x80x94, HOOCxe2x80x94, R2Nxe2x80x94, associated with the FBPase inhibitor, that cleave in vivo. Standard prodrugs include but are not limited to carboxylate esters where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of hydroxyl, thiol and amines where the group attached is Ian acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate. The groups illustrated are exemplary, not exhaustive, and one skilled in the art could prepare other known varieties of prodrugs. Such prodrugs of the compounds of formulae I and X, fall within the scope of the present invention. Prodrugs must undergo some form of a chemical transformation to produce the compound that is biologically active or is a precursor of the biologically active compound. In some cases, the prodrug is biologically active usually less than the drug itself, and serves to improve efficacy or safety through improved oral bioavailability, pharmacodynamic half-life, etc.
The term xe2x80x9cprodrug esterxe2x80x9d as employed herein includes, but is not limited to, the following groups and combinations of these groups:
[1] Acyloxyalkyl esters which are well described in the literature (Farquhar et al., J. Pharm. Sci. 72, 324-325 (1983)) and are represented by formula A 
wherein R, Rxe2x80x2, and Rxe2x80x3 are independently H, alkyl, aryl, alkylaryl, and alicyclic; (see WO 90/08155; WO 90/10636).
[2] Other acyloxyalkyl esters are possible in which an alicyclic ring is formed such as shown in formula B. These esters have been shown to generate phosphorus-containing nucleotides inside cells through a postulated sequence of reactions beginning with deesterification and followed by a series of elimination reactions (e.g. Freed et al., Biochem. Pharm. 38: 3193-3198 (1989)). 
wherein R is xe2x80x94H, alkyl, aryl, alkylaryl, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino, cycloalkyl, or alicyclic.
[3] Another class of these double esters known as alkyloxycarbonyloxymethyl esters, as shown in formula A, where R is alkoxy, aryloxy, alkylthio, arylthio, alkylamino, and arylamino; Rxe2x80x2, and Rxe2x80x3 are independently H, alkyl, aryl, alkylaryl, and alicyclic, have been studied in the area of xcex2-lactam antibiotics (Tatsuo Nishimura et al. J. Antibiotics, 1987, 40(1), 81-90; for a review see Ferres, H., Drugs of Today, 1983,19, 499.). More recently Cathy, M. S., et al. (Abstract from AAPS Western Regional Meeting, April, 1997) showed that these alkyloxycarbonyloxymethyl ester prodrugs on (9-[(R)-2-phosphonomethoxy)propyl]adenine (PMPA) are bioavailable up to 30% in dogs.
[4] Aryl esters have also been used as phosphonate prodrugs (e.g. Erion, DeLambert et al., J. Med. Chem. 37: 498, 1994; Serafinowska et al., J. Med. Chem. 38: 1372, 1995). Phenyl as well as mono and poly-substituted phenyl proesters have generated the parent phosphonic acid in studies conducted in animals and in man (Formula C). Another approach has been described where Y is a carboxylic ester ortho to the phosphate. Khamnei and Torrence, J. Med. Chem.; 39:4109-4115 (1996). 
wherein Y is H, alkyl, aryl, alkylaryl, alkoxy, acyloxy, halogen, amino, alkoxycarbonyl, hydroxy, cyano, and alicyclic.
[5] Benzyl esters have also been reported to generate the parent phosphonic acid. In some cases, using substituents at the para-position can accelerate the hydrolysis. Benzyl analogs with 4-acyloxy or 4-alkyloxy group [Formula D, Xxe2x95x90H, OR or O(CO)R or O(CO)OR] can generate the 4-hydroxy compound more readily through the action of enzymes, e.g. oxidases, esterases, etc. Examples of this class of prodrugs are described in Mitchell et al., J. Chem. Soc. Perkin Trans. I 2345 (1992); Brook, et al. WO 91/19721. 
wherein X and Y are independently H, alkyl, aryl, alkylaryl, alkoxy, acyloxy, hydroxy, cyano, nitro, perhaloalkyl, halo, or alkyloxycarbonyl; and
Rxe2x80x2 and Rxe2x80x3 are independently H, alkyl, aryl, alkylaryl, halogen, and alicyclic.
[6] Thio-containing phosphonate proesters have been described that are useful in the delivery of FBPase inhibitors to hepatocytes. These proesters contain a protected thioethyl moiety as shown in formula E. One or more of the oxygens of the phosphonate can be esterified. Since the mechanism that results in de-esterification requires the generation of a free thiolate, a variety of thiol protecting groups are possible. For example, the disulfide is reduced by a reductase-mediated process (Puech et al., Antiviral Res., 22: 155-174 (1993)). Thioesters will also generate free thiolates after esterase-mediated hydrolysis. Benzaria, et al., J. Med. Chem., 39:4958 (1996). Cyclic analogs are also possible and were shown to liberate phosphonate in isolated rat hepatocytes. The cyclic disulfide shown below has not been previously described and is novel. 
wherein Z is alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, or alkylthio.
Other examples of suitable prodrugs include proester classes exemplified by Biller and Magnin (U.S. Pat. No. 5,157,027); Serafinowska et al. (J. Med. Chem. 38, 1372 (1995)); Starrett et al. (J. Med. Chem. 37, 1857 (1994)); Martin et al. J. Pharm. Sci. 76, 180 (1987); Alexander et al., Collect. Czech. Chem. Commun, 59, 1853 (1994)); and EPO patent application 0 632 048 A1. Some of the structural classes described are optionally substituted, including fused lactones attached at the omega position (formulae E-1 and E-2) and optionally substituted 2-oxo-1,3-dioxolenes attached through a methylene to the phosphorus oxygen (formula E-3) such as: 
wherein R is xe2x80x94H, alkyl, cycloalkyl, or alicyclic; and
wherein Y is xe2x80x94H, alkyl, aryl, atkylaryl, cyano, alkoxy, acyloxy, halogen, amino, alicyclic, and alkoxycarbonyl.
The prodrugs of Formula E-3 are an example of xe2x80x9coptionally substituted alicyclic where the cyclic moiety contains a carbonate or thiocarbonate.xe2x80x9d
[7] Propyl phosphonate proesters can also be used to deliver FBPase inhibitors into hepatocytes. These proesters may contain a hydroxyl and hydroxyl group derivatives at the 3-position of the propyl group as shown in formula F. The R and X groups can form a cyclic ring system as shown in formula F. One or more of the oxygens of the phosphonate can be esterified. 
wherein R is alkyl, aryl, heteroaryl;
X is hydrogen, alkylcarbonyloxy, alkyloxycarbonyloxy; and
Y is alkyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, halogen, hydrogen, hydroxy, acyloxy, amino.
[8] Phosphoramidate derivatives have been explored as phosphate prodrugs (e.g. McGuigan et al., J. Med. Chem., 1999, 42: 393 and references cited therein) and phosphonate prodrugs (Bischofberger, et al., U.S. Pat. No. 5,798,340 and references cited therein) .as shown in Formulae G and H. 
Cyclic phosphoramidates have also been studied as phosphonate prodrugs because of their speculated higher stability compared to non-cyclic phosphoramidates (e.g. Starrett et al., J. Med. Chem., 1994, 37: 1857).
Another type of nucleotide prodrug was reported as the combination of S-acyl-2-thioethyl ester and phosphoramidate (Egron et al., Nucleosides and Nucleotides, 1999, 18, 981) as shown in Formula J. 
Other prodrugs are possible based on literature reports such as substituted ethyls for example, bis(trichloroethyl)esters as disclosed by McGuigan, et al. Bioorg Med. Chem. Lett., 3:1207-1210 (1993), and the phenyl and benzyl combined nucleotide esters reported by Meier, C. et al. Bioorg. Med. Chem. Lett., 7:99-104 (1997).
The structure 
has a plane of symmetry running through the phosphorus-oxygen double bond when R6xe2x95x90R6, Vxe2x95x90W, Wxe2x80x2xe2x95x90H, and V and W are either both pointing up or both pointing down. The same is true of structures where each xe2x80x94NR6 is replaced with xe2x80x94Oxe2x80x94.
The term xe2x80x9ccyclic 1xe2x80x2,3xe2x80x2-propane esterxe2x80x9d, xe2x80x9ccyclic 1,3-propane esterxe2x80x9d, xe2x80x9ccyclic 1xe2x80x2,3xe2x80x2-propanyl esterxe2x80x9d, and xe2x80x9ccyclic 1,3-propanyl esterxe2x80x9d refers to the following: 
The phrase xe2x80x9ctogether V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally containing 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorusxe2x80x9d includes the following: 
The structure shown above (left) has an additional 3 carbon atoms that forms a five member cyclic group. Such cyclic groups must possess the listed substitution to be oxidized.
The phrase xe2x80x9ctogether V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, that is fused to an aryl group attached at the beta and gamma position to the Y attached to the phosphorusxe2x80x9d includes the following: 
The phrase xe2x80x9ctogether V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorusxe2x80x9d includes the following: 
The structure above has an acyloxy substituent that is three carbon atoms from a Y, and an optional substituent, xe2x80x94CH3, on the new 6-membered ring. There has to be at least one hydrogen at each of the following positions: the carbon attached to Z; both carbons alpha to the carbon labelled xe2x80x9c3xe2x80x9d; and the carbon attached to xe2x80x9cOC(O)CH3xe2x80x9d above.
The phrase xe2x80x9ctogether W and Wxe2x80x2 are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroarylxe2x80x9d includes the following: 
The structure above has V=aryl, and a spiro-fused cyclopropyl group for W and Wxe2x80x2.
The term xe2x80x9ccyclic phosph(oramid)atexe2x80x9d refers to 
where Y is independently xe2x80x94Oxe2x80x94 or xe2x80x94NR6xe2x80x94. The carbon attached to V must have a Cxe2x80x94H bond. The carbon attached to Z must also have a Cxe2x80x94H bond.
The term xe2x80x9cenhancingxe2x80x9d refers to increasing or improving a specific property.
The term xe2x80x9cenhanced oral bioavailabilityxe2x80x9d refers to an increase of at least 50% of the absorption of the dose of the parent drug or prodrug(not of this invention) from the gastrointestinal tract. More preferably it is at least 100%. Measurement of oral bioavailability usually refers to measurements of the prodrug, drug, or drug metabolite in blood, tissues, or urine following oral administration compared to measurements following systemic administration.
The term xe2x80x9cparent drugxe2x80x9d refers to any compound which delivers the same biologically active compound. The parent drug form is Mxe2x80x94Xxe2x80x94P(O)(OH)2 and standard prodrugs, such as esters.
The term xe2x80x9cdrug metabolitexe2x80x9d refers to any compound produced in vivo or in vitro from the parent drug, which can include the biologically active drug.
The term xe2x80x9cpharmacodynamic half-lifexe2x80x9d refers to the time after administration of the drug or prodrug to observe a diminution of one half of the measured pharmacological response. Pharmacodynamic half-life is enhanced when the half-life is increased by preferably at least 50%.
The term xe2x80x9cpharmacokinetic half-lifexe2x80x9d refers to the time after administration of the drug or prodrug to observe a dimunition of one half of the drug concentration in plasma or tissues.
The term xe2x80x9ctherapeutic indexxe2x80x9d refers to the ratio of the dose of a drug or prodrug that produces a therapeutically beneficial response relative to the dose that produces an undesired response such as death, an elevation of markers that are indicative of toxicity, and/or pharmacological side effects.
The term xe2x80x9cbiologically active drug or agentxe2x80x9d refers to the chemical entity that produces a biological effect. Thus, active drugs or agents include compounds which as Mxe2x80x94Xxe2x80x94P(O)(OH)2 are biologically active.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d refers to an amount that has any beneficial effect in treating a disease or condition.
FBPase inhibitors used in the invention are compounds that inhibit human FBPase activity (Example A), inhibit glucose production from hepatocytes (Examples C and D), lower glucose levels in fasted animals (Examples E-F), and decrease blood glucose levels in diabetic animal models (Examples N-T).
Insulin sensitizers used in this invention are compounds that alter the body""s response to endogenous or exogeneous insulin or insulin-like molecules. This reponse can include an improvement in whole-body glucose disposal, a reduction in hepatic glucose output, an increase in insulin-mediated glycogenesis, and other manifestations of improved peripheral insulin resistance. In some instances, the insulin sensitizers used in this invention may also lower circulating triglycerides and/or free fatty acids, may increase HDL cholesterol levels, may reduce hyperinsulinemia, or may improve the pancreatic insulin secretory response. Examples of insulin sensitizers include compounds that activate or are agonists of the PPARxcex3 receptor, are ligands of RXR that activate transcriptional activity of the RXR:PPAR xcex3 heterodimer, or are compounds that achieve enhanced insulin sensitivity through modulation of enzyme activities in cell signalling pathways associated with insulin receptor activation. Enzymes in the latter pathways include protein kinase C, tyrosine phosphatase, PI-3-kinase, MAP kinase, and others. The insulin sensitizers used in this invention have affinity for PPARxcex31, PPARxcex32, and/or other isoforms of the PPARxcex3 family, and contain either a thiazolidinedione ring structure, a modified thiazolidinedione ring structure, or have a structure that is unrelated to the thiazolidinediones (eg. the 3-aryl-2-alkoxy propanoic acids). The insulin sensitizers also include compounds with affinity for RXRxcex1, RXRxcex2, RXRxcex3 and/or other RXR receptor isoforms, and are either retinoids such as 9-cis-retinoic acid and its analogs, rexinoids such as (tetramethyltetrahydronaphthyl)carbonylbenzoic acid analogs, or are of other structural classes. Insulin sensitizers used in this invention typically exhibit activity in assays known to be useful for characterizing compounds that act as insulin sensitizers. The assays include but are not limited to: (a) PPARxcex3 binding assays; (b) RXR or RXR-PPARxcex3 activation assays (eg. co-transfection or cis-trans assays); (c) insulin signaling assays such as those measuring receptor or signaling protein phosphorylation/expression (d) adipocyte binding assays; (e) glucose uptake assays in adipocytes or L6 myocytes; (f) adipocyte differentiation assays using triglyceride accumulation, glucose oxidation, or fat/carbohydrate metabolism gene expression as indeces; (g) insulin secretion assays in beta cell islets or the perfused pancreas; (h) pancreatic islet histology assays; (i) in vivo glucose disposal assays; (j) whole body insulin sensitivity assays using the in vivo hyperinsulinemic-glucose clamp technique; (k) hepatic glucose output assays utilizing labeling or NMR techniques; and (l) antihyperglycemic and/or triglyceride/free fatty acid lowering activity in animal models of diabetes such as the KK, ob/ob, or db/db mouse or the ZDF rat.
The instant invention is a combination therapy and a composition for the treatment for diabetes and diseases responding to increased glycemic control or to decreased insulin levels. The combination therapy consists of administering one or more FBPase inhibitors and one or more agents known to enhance insulin action, i.e. an insulin sensitizer agent. Known insulin sensitizers include thiazolidinediones, PPAR xcex3 agonists, RXR ligands and inhibitors of the RAX system or angiotensin II action. The therapy is useful for treating diseases characterized by hyperglycemia, impaired glucose tolerance or insulin resistance. Such diseases include diabetes, obesity, hypertension, impaired glucose tolerance and polycystic ovarian syndrome, pancreatitis and renal disease.
In some cases, the combined therapy provides a method for improved glycemic control. The combined therapy will provide improved therapy for one or more of these conditions relative to either agent alone. The combined therapy provides a method for improved glycemic control in NIDDM subjects beyond that achievable by either agent alone. The combined therapy can result in decreases in hepatic glucose output beyond that observed for glucose-lowering doses of the insulin sensitizer agent. Furthermore, the combined therapy can result in improvements in insulin resistance and/or insulin secretion beyond that observed for FBPase inhibitors. In other cases, combining an insulin sensitizer with an FBPase inhibitor or visa versa has an insignificant effect on glycemia but instead results in an improved therapy by minimizing potential adverse pharmacologies sometimes associated with FBPase and insulin sensitizer therapies. For example, FBPase therapy may be associated with elevations of lactate, tryglicerides, free fatty acids or potential side-effects resulting from the renal clearance of the inhibitor. Insulin sensitizer therapy is known to be associated with weight gain, elevation of liver enzymes, and reductions in heamatocrit. In still another aspect of the invention is that the combination therapy achieves similar benefits as observed with one or the other therapies alone but at significantly lower doses. The lower doses improve or eliminate side effects and/or toxicologies associated with the individual drug treatment. The combined therapy entails administration to the host the agents either separately or simultaneously.
Most preferred would be the administration of both agents simultaneously in either the same capsule or as separate pills. Another preferred embodiment is the administration of both agents during meal time (just prior to feeding or just after feeding). Another preferred embodiment is the administration of the insulin sensitizer during meal time and the FBPase inhibitor during times of fasting such as at bed time.
The compounds of the invention may be administered for therapy by any suitable route including, oral, rectal, nasal, topical, vaginal, parenteral (including subcutaneous, intramuscular, intravenous and intradermal) and transdermal. The preferred route is oral.
The present invention relates to methods and compositions for treating a host having NIDDM or a condition associated with insulin resistance by administering to the host a composition containing a pharmaceutically effective amount of an agent that enhances insulin sensitivity and a pharmaceutically effective amount of an FBPase inhibitor. The compositions of this invention are adapted to cure, improve or prevent one or more symptoms of NIDDM. A preferred drug combination will have high potency and low toxicity as can be determined by standard pharmaceutical procedures in cell cultures or experimental animal models, e.g. by determining the LD50 and the ED50.
Preferred FBPase inhibitors encompassed by the instant invention are compounds that inhibit enzyme activity as determined by conducting in vitro inhibition studies (Examples A-D). In some cases, in vivo metabolic activation of a compound may be required to generate the FBPase inhibitor. This class of compounds may be inactive in the enzyme inhibition screen (Example A), may or may not be active in hepatocytes (Examples C and D), but is active in vivo as evidenced by glucose lowering in the normal, fasted rat (Examples E and F) and/or in animal models of diabetes (Examples N-T).
Although the present invention is not limited to the following structures, the FBPase inhibitors generally are of the following formulae: 
Suitable alkyl groups include groups having from 1 to about 20 carbon atoms. Suitable aryl groups include groups having from 1 to about 20 carbon atoms. Suitable aralkyl groups include groups having from 2 to about 21 carbon atoms. Suitable acyloxy groups include groups having from 1 to about 20 carbon atoms. Suitable alkylene groups include groups having from 1 to about 20 carbon atoms. Suitable alicyclic groups include groups having 3 to about 20 carbon atoms. Suitable heteroaryl groups include groups having from 1 to about 20 carbon atoms and from 1 to 4 heteroatoms, preferably independently selected from nitrogen, oxygen, phosphorous, and sulfur. Suitable heteroalicyclic groups include groups having from 2 to about twenty carbon atoms and from 1 to 5 heteroatoms, preferably independently selected from nitrogen, oxygen, phosphorous, and sulfur.
Preferred are the following compounds of formula IA 
wherein in vivo or in vitro compounds of formula IA are converted to Mxe2x80x94PO32xe2x88x92 which is an inhibitor of fructose -1,6-bisphosphatase and
n is an integer from 1 to 3;
R18 is independently selected from the group consisting of H, lower alkyl, aryl, aralkyl, or together with R12 is connected via 1-4 carbon atoms to form a cyclic group;
each R12 and R13 is independently selected from the group consisting of H, lower alkyl, lower aryl, lower aralkyl, all optionally substituted, or R12 and R13 together are connected via 2-6 carbon atoms to form a cyclic group;
each R14 is independently selected from the group consisting of xe2x80x94OR17, xe2x80x94N(R17)2, xe2x80x94NHR17, and xe2x80x94SR17;
R15 is selected from the group consisting of xe2x80x94H, lower alkyl, lower aryl, lower arakyl, or together with R16 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
16 R is selected from the group consisting of xe2x80x94(CR12R13)nxe2x80x94C(O)xe2x80x94R14, lower alkyl, lower aryl, lower aralkyl, or together with R15 is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
each R17 is independently selected from the group consisting of lower alkyl, lower aryl, and lower aralkyl, or together R17 and R17 on N is connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S;
and pharmaceutically acceptable salts thereof.
More preferred are FBPase inhibitors where Mxe2x80x94PO32xe2x88x92 has an IC50 on isolated human FBPase enzyme of less than or equal to 5 xcexcM. Especially preferred are such compounds that bind to the AMP site of FBPase.
In one aspect, preferred are compounds of formula IA or formula I wherein M is R5xe2x80x94Xxe2x80x94
wherein
R5 is selected from the group consisting of: 
wherein:
each G is independently selected from the group consisting of C, N, O, S, and Se, and wherein only one G may be O, S, or Se, and at most one G is N;
each Gxe2x80x2 is independently selected from the group consisting of C and N and wherein no more than two Gxe2x80x2 groups are N;
A is selected from the group consisting of xe2x80x94H, xe2x80x94NR42, xe2x80x94CONR42, xe2x80x94CO2R3, halo, xe2x80x94S(O)R3, xe2x80x94SO2R3, alkyl, alkenyl, alkynyl, perhaloalkyl, haloalkyl, aryl, xe2x80x94CH2OH, xe2x80x94CH2NR42, xe2x80x94CH2CN, xe2x80x94CN, xe2x80x94C(S)NH2, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94N3, xe2x80x94NHC(S)NR42, xe2x80x94NHAc, and null;
each B and D are independently selected from the group consisting of xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, xe2x80x94C(O)R11, xe2x80x94C(O)SR3, xe2x80x94SO2R11, xe2x80x94S(O)R3, xe2x80x94CN, xe2x80x94NR92, xe2x80x94OR3, xe2x80x94SR3, perhaloalkyl, halo, xe2x80x94NO2, and null, all except xe2x80x94H, xe2x80x94CN, perhaloalkyl, xe2x80x94NO2, and halo are optionally substituted;
E is selected from the group consisting of xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, xe2x80x94C(O)OR3, xe2x80x94CONR42, xe2x80x94CN, xe2x80x94NR92, xe2x80x94NO2, xe2x80x94OR3, xe2x80x94SR3, perhaloalkyl halo, and null, all except xe2x80x94H, xe2x80x94CN, perhaloalkyl, and halo are optionally substituted;
J is selected from the group consisting of xe2x80x94H and null;
X is an optionally substituted linking group that links R5 to the phosphorus atom via 2-4 atoms, including 0-1 heteroatoms selected from N, O, and S, except that if X is urea or carbamate there is 2 heteroatoms, measured by the shortest path between R5 and the phosphorus atom, and wherein the atom attached to the phosphorus is a carbon atom, and wherein X is selected from the group consisting of -alkyl(hydroxy)-, -alkynyl-, -heteroaryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X is not substituted with xe2x80x94COOR2, xe2x80x94SO3H, or xe2x80x94PO3R22;
R2 is selected from the group consisting of R3 and xe2x80x94H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
each R4 is independently selected from the group consisting of xe2x80x94H, and alkyl, or together R4 and R4 form a cyclic alkyl group;
each R9 is independently selected from the group consisting of xe2x80x94H, alkyl, aralkyl, and alicyclic, or together R9 and R9 form a cyclic alkyl group;
R11 is selected from the group consisting of alkyl, aryl, xe2x80x94NR22, and xe2x80x94OR2; and with the proviso that:
1) when Gxe2x80x2 is N, then the respective A, B, D, or E is null;
2) at least one of A and B, or A, B, D, and E is not selected from the group consisting of xe2x80x94H or null;
3) when R5 is a six-membered ring, then X is not any 2 atom linker, an optionally substituted -alkyloxy-, or an optionally substituted -alkylthio-;
4) when G is N, then the respective A or B is not halogen or a group directly bonded to G via a heteroatom;
5) when X is not a -heteroaryl- group, then R5 is not substituted with two or more aryl groups;
and pharmaceutically acceptable prodrugs and salts thereof.
More preferred are such compounds wherein when R5 is 2-thiazolyl, 2-oxazolyl, or 2-selenazolyl, and X is -alkoxyalkyl-, -alkylthioalkyl-, -alkyloxy-, or -alkylthio-, then A is not xe2x80x94CONH2 and B is not xe2x80x94H. Also more preferred are such compounds wherein when R5 is 2-thiazolyl, 2-oxazolyl, or 2-selenazolyl, then X is not -alkyloxyalkyl-, -alkylthioalkyl-, -alkyloxy-, or -alkylthio-.
Preferably, compounds of formula IA have an IC50 ofxe2x89xa650 xcexcM on glucose production in isolated rat hepatocytes.
More preferred R5 groups include pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, pyrazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, and 1,3-selenazolyl, all of which contain at least one substituent. Preferably, R5 is not 2-thiazolyl, or 2-oxazolyl.
In one aspect, preferred R5 groups are substituted with the following groups:
A is selected from the group consisting of xe2x80x94H, xe2x80x94NR42, xe2x80x94CONR42, xe2x80x94CO2R3, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl, C1-C6 haloalkyl, aryl, xe2x80x94CH2OH, xe2x80x94CH2NR42, xe2x80x94CH2CN, xe2x80x94CN, xe2x80x94C(S)NH2, xe2x80x94OR4, xe2x80x94SR4, xe2x80x94N3, xe2x80x94NHC(S)NR42, xe2x80x94NHAc, and null;
each B and D are independently selected from the group consisting of xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, xe2x80x94C(O)R11, xe2x80x94C(O)SR3, xe2x80x94SO2R11, xe2x80x94S(O)R3, xe2x80x94CN, xe2x80x94NR22, xe2x80x94OR3, xe2x80x94SR3, perhaloalkyl, halo, and null, all except xe2x80x94H, xe2x80x94CN, perhaloalkyl, and halo are optionally substituted;
E is selected from the group consisting of xe2x80x94H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, C4-C6 alicyclic, alkoxyalkyl, xe2x80x94C(O)OR3, xe2x80x94CONR42, xe2x80x94CN, xe2x80x94NR92, xe2x80x94OR3, xe2x80x94SR3, C1-C6 perhaloalkyl, halo, and null, all except xe2x80x94H, xe2x80x94CN, perhaloalkyl, and halo are optionally substituted; and
each R4 is independently selected from the group consisting of xe2x80x94H, and C1-C2 alkyl.
In another aspect, preferred are compounds wherein R5 is: 
In another aspect, preferred are compounds wherein R5 is: 
More preferred are compounds wherein R5 is selected from the group consisting of: 
wherein
Axe2x80x3 is selected from the group consisting of xe2x80x94H, xe2x80x94NR42, xe2x80x94CONR42, xe2x80x94CO2R3, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl, C1-C6 haloalkyl, aryl, xe2x80x94CH2OH, xe2x80x94CH2NR42, xe2x80x94CH2CN, xe2x80x94CN, xe2x80x94C(S)NH2, xe2x80x94OR3, xe2x80x94SR1, xe2x80x94N3, xe2x80x94NHC(S)NR42, and xe2x80x94NHAc;
Bxe2x80x3 and Dxe2x80x3 are independently selected from the group consisting of xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, xe2x80x94C(O)R11, xe2x80x94C(O)SR3, xe2x80x94SO2R11, xe2x80x94S(O)R3, xe2x80x94CN, xe2x80x94NR92, xe2x80x94OR3, xe2x80x94SR3, perhaloalkyl, and halo, all except xe2x80x94H, xe2x80x94CN, perhaloalkyl, and halo are optionally substituted;
Exe2x80x3 is selected from the group consisting of xe2x80x94H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C4-C6 alicyclic, alkoxyalkyl, xe2x80x94C(O)OR3, xe2x80x94CONR42, xe2x80x94CN, xe2x80x94NR92, xe2x80x94OR3, xe2x80x94SR3, C1-C6 perhaloalkyl, and halo, all except H, xe2x80x94CN, perhaloalkyl, and halo are optionally substituted; and
each R4 is independently selected from the group consisting of xe2x80x94H and C1-C2 alkyl.
Especially preferred are those compounds of formula V-1A and formula V-2A wherein
Axe2x80x3 is selected from the group consisting of xe2x80x94NH2, xe2x80x94CONH2, halo, xe2x80x94CH3, xe2x80x94CF3, xe2x80x94CH2-halo, xe2x80x94CN, xe2x80x94OCH3, xe2x80x94SCH3, and xe2x80x94H;
Bxe2x80x3 is selected from the group consisting of xe2x80x94H, xe2x80x94C(O)R11, xe2x80x94C(O)SR3, alkyl, aryl, alicyclic, halo, xe2x80x94CN, xe2x80x94SR3, OR3 and xe2x80x94NR92;
Dxe2x80x3 is selected from the group consisting of xe2x80x94H, xe2x80x94C(O)R11, xe2x80x94C(O)SR3, xe2x80x94NR92, alkyl, aryl, alicyclic, halo, and xe2x80x94SR3;
Exe2x80x3 is selected from the group consisting of xe2x80x94H, C1-C6 alkyl, lower alicyclic, halo, xe2x80x94CN, xe2x80x94C(O)OR3, and xe2x80x94SR3.
Exe2x80x3 is selected from the group consisting of -heteroaryl-, -alkoxycarbonyl-, and -alkylaminocarbonyl-, all optionally substituted;
R18 and R15 are selected from the group consisting of H, and methyl;
R2 is selected from the group consisting of R3 and xe2x80x94H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
each R12 and R13 is independently selected from the group consisting of xe2x80x94H, methyl, i-propyl, i-butyl, and benzyl, or together R12 and R13 are connected via 2-5 carbon atoms to form a cycloalkyl group;
n is 1;
R14 is xe2x80x94OR17;
R16 is xe2x80x94(CR12R13)nxe2x80x94C(O)xe2x80x94R14; and
R17 is selected from the group consisting of methyl, ethyl, propyl, phenyl, and benzyl. Most preferred are such compounds with 
wherein C* has S stereochemistry.
Also particularly preferred are such compounds wherein R5 is selected from the group consisting of: 
Also particularly preferred are such compounds wherein R5 is selected from the group consisting of: 
Also particularly preferred are such compounds wherein R5 is selected from the group consisting of: 
In one especially preferred aspect, R5 is 
X is selected from the group consisting of methylenoxycarbonyl, and furan-2,5-diyl, and pharmaceutically acceptable salts and prodrugs thereof. More preferred are such compounds wherein Axe2x80x3 is xe2x80x94NH2, X is furan-2,5-diyl, and Bxe2x80x3 is xe2x80x94S(CH2)2CH3; wherein Axe2x80x3 is xe2x80x94NH2, X is furan-2,5-diyl, and Bxe2x80x3 is xe2x80x94CH2xe2x80x94CH(CH3)2; wherein Axe2x80x3 is xe2x80x94NH2, X is furan-2,5-diyl, and Bxe2x80x3 is xe2x80x94COOEt; wherein Axe2x80x3 is xe2x80x94NH2, X is furan-2,5-diyl, and Bxe2x80x3 is xe2x80x94SMe; or wherein Axe2x80x3 is xe2x80x94NH2, X is methyleneoxycarbonyl, and Bxe2x80x3 is xe2x80x94CH(CH3)2.
Most preferred are such thiazoles where Axe2x80x3 is xe2x80x94NH2, X is furan-2,5-diyl, Bxe2x80x3 is xe2x80x94S(CH2)2CH3 and wherein 
wherein C* has S stereochemistry.
Also most preferred are such thiazoles where Axe2x80x3 is xe2x80x94NH2, X is furan-2,5-diyl, Bxe2x80x3 is xe2x80x94CH2xe2x80x94CH(CH3)2, and wherein 
wherein C* has S stereochemistry.
In another preferred aspect, R5 is 
X is selected from the group consisting of furan-2,5-diyl, and methyleneoxycarbonyl, Axe2x80x3 is xe2x80x94NH2, and pharmaceutically acceptable salts and prodrugs thereof. More preferred are such compounds wherein X is furan -2,5-diyl, and Bxe2x80x3 is xe2x80x94SCH2CH2CH3.
In another preferred aspect, R5 is 
Axe2x80x3 is xe2x80x94NH2, Exe2x80x3 and Dxe2x80x3 are xe2x80x94H, Bxe2x80x3 is selected from the group consisting of cyclopropyl, and n-propyl, X is selected from the group consisting of methyleneoxycarbonyl, and furan-2,5-diyl, and pharmaceutically acceptable salts and prodrugs thereof.
In another preferred aspect, R5 is 
Axe2x80x3 is xe2x80x94NH2, Dxe2x80x3 is xe2x80x94H, Bxe2x80x3 is selected from the group consisting of n-propyl, and cyclopropyl, X is selected from the group consisting of furan-2,5-diyl, and methyleneoxycarbonyl, and pharmaceutically acceptable salts and prodrugs thereof.
Preferred groups include -heteroaryl-, -alkylcarbonylamino-, -alkylaminocarbonyl-, and -alkoxycarbonyl-. More preferred is -heteroaryl-, and -alkoxycarbonyl-.
The compounds of formula 1A are preferred. 
More preferred are compounds of formulae VII or IX: 
Preferred Axe2x80x3 groups include xe2x80x94NH2, xe2x80x94CONH2, halo, xe2x80x94CH3, xe2x80x94CF3, xe2x80x94CH2-halo, xe2x80x94CN, xe2x80x94OCH3, xe2x80x94SCH3, and xe2x80x94H.
More preferred Axe2x80x3 groups include xe2x80x94NH2, xe2x80x94Cl, xe2x80x94Br, and xe2x80x94CH3.
Preferred Bxe2x80x3 groups include xe2x80x94H, xe2x80x94C(O)R11, xe2x80x94C(O)SR3, alkyl, aryl, alicyclic, halo, xe2x80x94CN, xe2x80x94SR3, xe2x80x94NR92, and xe2x80x94OR3. More preferred is xe2x80x94H, xe2x80x94C(O)OR3, xe2x80x94C(O)SR3, C1-C6 alkyl, alicyclic, halo, heteroaryl, and xe2x80x94SR.
Preferred Dxe2x80x3 groups include xe2x80x94H, xe2x80x94C(O)R11, xe2x80x94C(O)SR3, alkyl, aryl, alicyclic, halo, xe2x80x94NR92, and xe2x80x94SR3. More preferred is xe2x80x94H, xe2x80x94C(O)OR3, lower alkyl, alicyclic, and halo.
Preferred Exe2x80x3 groups include xe2x80x94H, C1-C6 alkyl, lower alicyclic, halogen, xe2x80x94CN, xe2x80x94C(O)OR3, xe2x80x94SR3, and xe2x80x94CONR42. More preferred is xe2x80x94H, xe2x80x94Br, and xe2x80x94Cl.
Preferred R18 groups include xe2x80x94H, methyl, and ethyl. More preferred is xe2x80x94H and methyl. Especially preferred is xe2x80x94H.
Preferred compounds include those wherein each R12 and R13 is independently selected from the group consisting of xe2x80x94H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, xe2x80x94CH2CH2xe2x80x94SCH3, phenyl, and benzyl, or together R12 and R13 are connected via 2-5 carbon atoms to form a cycloalkyl group. More preferred is each R12 and R13 is independently selected from the group consisting of xe2x80x94H, methyl, i-propyl, i-butyl, and benzyl, or together R12 and R13 are connected via 2-5 carbon atoms to form a cycloalkyl group. Also more preferred are such compounds wherein each R12 and R13 is independently selected from the group consisting of xe2x80x94H, methyl, i-propyl, and benzyl, or together R12 and R13 are connected via 4 carbon atoms to form a cyclopentyl group. Especially preferred are those compounds wherein R12 and R13 are both xe2x80x94H, both methyl, or R12 is H and R13 is selected from the group consisting of methyl, i-propyl, and benzyl. Most preferred are such compounds wherein n is 1, and R is xe2x80x94H, then the carbon attached to R12 and R13 has S stereochemistry.
Preferably, n is an integer of from 1-2. More preferred is when n is 1.
Preferred compounds include those wherein each R14 is independently selected from the group consisting of xe2x80x94OR17, and xe2x80x94SR17; and R17 is selected from the group consisting of optionally substituted methyl, ethyl, propyl, t-butyl, and benzyl. More preferred are such compounds wherein each R14 is independently selected from the group consisting of xe2x80x94OR17; and R17 is selected from the group consisting of methyl, ethyl, propyl, and benzyl. Most preferred are such compounds wherein R17 is selected from the group consisting of ethyl, and benzyl.
Preferred are compounds wherein R15 is not H. More preferred are compounds wherein R15 and R16 are independently selected from the group consisting of lower alkyl, and lower aralkyl, or together R15 and R16 are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S. Also more preferred are compounds wherein R15 and R16 are independently selected from the group consisting of C1-C6 alkyl, or together R15 and R16 are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S. In one aspect, particularly preferred are compounds wherein xe2x80x94N15R16 is a cyclic amine. Especially preferred are such compounds wherein xe2x80x94NR15R16 is selected from the group consisting of morpholinyl and pyrrolidinyl.
Preferred are compounds where R16 is xe2x80x94(CR12R13)nxe2x80x94C(O)xe2x80x94R14. Particularly preferred are such compounds that are of the formula: 
More preferred are such compounds wherein n is 1. Especially preferred are such compounds wherein when R12 and R13 are not the same, then H2Nxe2x80x94CR12R13xe2x80x94C(O)xe2x80x94R14 is an ester, or thioester of a naturally occurring amino acid; and R14 is selected from the group consisting of xe2x80x94OR17 and xe2x80x94SR17.
More preferred are compounds where n is 1 and wherein
R18 is selected from the group consisting of xe2x80x94H, methyl, and ethyl;
R12 and R13 are independently selected from the group consisting of xe2x80x94H, methyl, i-propyl, i-butyl, and benzyl, or together are connected via 2-5 carbon atoms to form a cycloalkyl group;
R14 is OR17;
R17 is selected from the group consisting of methyl, ethyl, propyl, t-butyl, and benzyl; and
R15 and R16 are independently selected from the group consisting of lower alkyl, and lower aralkyl, or together R15 and R16 are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, and N.
In one aspect, preferred are compounds of Formula IA wherein M is 
wherein:
Gxe2x80x3 is selected from the group consisting of xe2x80x94Oxe2x80x94 and xe2x80x94Sxe2x80x94;
A2, L2, E2, and J2 are selected from the group consisting of xe2x80x94N42, xe2x80x94NO2, xe2x80x94H, xe2x80x94OR2, xe2x80x94SR2, xe2x80x94C(O)NR42, halo, xe2x80x94COR11, xe2x80x94SO2R3, guanidinyl, amidinyl, aryl, aralkyl, alkyoxyalkyl, xe2x80x94SCN, xe2x80x94NHSO2R9, xe2x80x94SO2NR42, xe2x80x94CN, xe2x80x94S(O)R3, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together L2 and E2 or E2 and J2 form an annulated cyclic group;
X2 is selected from the group consisting of xe2x80x94CR22xe2x80x94, xe2x80x94CF2xe2x80x94, xe2x80x94OCR22xe2x80x94, xe2x80x94SCR22xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94Sxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(S)xe2x80x94; and xe2x80x94NR19CR22xe2x80x94, and wherein in the atom attached to the phosphorus is a carbon atom; with the proviso that X2 is not substituted with xe2x80x94COOR2, xe2x80x94SO3H, or xe2x80x94PO3R22;
R is selected from the group consisting of R3 and xe2x80x94H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
each R4 is independently selected from the group consisting of xe2x80x94H, and alkyl, or together R4 and R4 form a cyclic alkyl group;
each R9 is independently selected from the group consisting of xe2x80x94H, alkyl, aralkyl, and alicyclic, or together R9 and R9 form a cyclic alkyl group;
R11 is selected from the group consisting of alkyl, aryl, xe2x80x94NR22, and xe2x80x94OR2;
R19 is selected from the group consisting of lower alkyl, xe2x80x94H, and xe2x80x94COR2; and
pharmaceutically acceptable prodrugs and salts thereof. More preferred are compounds wherein Gxe2x80x3 is xe2x80x94Sxe2x80x94. Most preferred are compounds wherein A2, L2, E2, and J2 are independently selected from the group consisting of xe2x80x94H, xe2x80x94NR42, xe2x80x94Sxe2x80x94Cxe2x89xa1N, halogen, xe2x80x94OR3, hydroxy, -alkyl(OH), aryl, alkyloxycarbonyl, xe2x80x94SR3, lower perhaloalkyl, and C1-C5 alkyl, or together L2 and E2 form an annulated cyclic group. More preferably A2, L2, E2 and J2 are independently selected from the group consisting of xe2x80x94H, xe2x80x94NR42, xe2x80x94Sxe2x80x94Cxe2x89xa1N, halogen, lower alkoxy, hydroxy, lower alkyl(hydroxy), lower aryl, and C1-C5 alkyl, or together L2 and E2 form an annulated cyclic group.
Most preferred A2 groups include xe2x80x94NH2, xe2x80x94H, halo, and C1-C5 alkyl.
Most preferred L2 and E2 groups are those independently selected from the group consisting of xe2x80x94H, xe2x80x94Sxe2x80x94Cxe2x89xa1N, lower alkoxy, C1-C5 alkyl, lower alkyl(hydroxy), lower aryl, and halogen or together L2 and E2 form an annulated cyclic group containing an additional 4 carbon atoms.
Most preferred J2 groups include xe2x80x94H, and C1-C5 alkyl.
Preferred X2 groups include xe2x80x94CF2xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94OC(O)xe2x80x94 xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94NHCH2xe2x80x94, and xe2x80x94N(C(O)CH3)xe2x80x94CH2xe2x80x94. More preferred are xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, and xe2x80x94N(C(O)CH3)xe2x80x94CH2xe2x80x94. Most preferred is xe2x80x94OCH2xe2x80x94.
One preferred aspect include compound wherein A2 is selected from the group consisting of xe2x80x94H, xe2x80x94NH2, xe2x80x94CH3, xe2x80x94Cl, and xe2x80x94Br;
L2 is xe2x80x94H, lower alkyl, halogen, lower alkyloxy, hydroxy, -alkenylene-OH, or together with E2 forms a cyclic group including aryl, cyclic alkyl, heteroaryls, heterocyclic alkyl;
E2 is selected from the groups consisting of H, lower alkyl, halogen, SCN, lower alkyloxycarbonyl, lower alkyloxy, or together with L2 forms a cyclic group including aryl, cyclic alkyl, heteroaryl, or heterocyclic alkyl;
J2 is selected from the groups consisting of H, halogen, and lower alkyl;
Gxe2x80x3 is xe2x80x94Sxe2x80x94;
X2 is xe2x80x94OCH2xe2x80x94;
and pharmaceutically acceptable salts and prodrugs thereof. More preferred are such compounds wherein
R18 is selected from the group consisting of xe2x80x94H, methyl, and ethyl;
R12 and R13 are independently selected from the group consisting of xe2x80x94H, methyl, i-propyl, i-butyl, and benzyl, or together are connected via 2-5 carbon atoms to form a cycloalkyl group;
R14 is xe2x80x94OR17;
R17 is selected from the group consisting of methyl, ethyl, propyl, t-butyl, and benzyl; and
R15 and R16 are independently selected from the group consisting of lower alkyl, and lower aralkyl, or together R15 and R16 are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, and N.
Also more preferred are such compounds where A2 is NH2, L2 is selected from the group consisting of xe2x80x94Et and xe2x80x94Cl, E2 is selected from the group consisting of xe2x80x94SCN, xe2x80x94Et, and xe2x80x94Br, and J2 is xe2x80x94H. Particularly preferred are such compounds wherein 
is selected from the group consisting of 
wherein C* has S stereochemistry.
Preferred R18 groups include xe2x80x94H, methyl, and ethyl. More preferred is xe2x80x94H and methyl. Especially preferred is xe2x80x94H.
Preferred compounds include those wherein each R12 and R13 is independently selected from the group consisting of xe2x80x94H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, xe2x80x94CH2CH2xe2x80x94SCH3, phenyl, and benzyl, or together R12 and R13 are connected via 2-5 carbon atoms to form a cycloalkyl group. More preferred is each R12 and R13 is independently, selected from the group consisting of xe2x80x94H, methyl, i-propyl, i-butyl, and benzyl, or together R12 and R13 are connected via 2-5 carbon atoms to form a cycloalkyl group. Also more preferred are such compounds wherein each R12 and R13 is independently selected from the group consisting of xe2x80x94H, methyl, i-propyl, and benzyl, or together R12 and R13 are connected via 4 carbon atoms to form a cyclopentyl group. Especially preferred are those compounds wherein R12 and R3 are both xe2x80x94H, both methyl, or R12 is H and R3 is selected from the group consisting of methyl, i-propyl, and benzyl. Most preferred are such compounds wherein n is 1, and R12 is xe2x80x94H, then the carbon attached to R12 and R13 has S stereochemistry.
Preferably, n is an integer of from 1-2. More preferred is when n is 1.
Preferred compounds include those wherein each R14 is independently selected from the group consisting of xe2x80x94OR17, and xe2x80x94SR17; and R17 is selected from the group consisting of optionally substituted methyl, ethyl, propyl, t-butyl, and benzyl. More preferred are such compounds wherein each R14 is independently selected from the group consisting of xe2x80x94OR17; and R17 is selected from the group consisting of methyl, ethyl, propyl, and benzyl. Most preferred are such compounds wherein R17 is selected from the group consisting of ethyl, and benzyl.
Preferred are compounds wherein R15 is not H. More preferred are compounds wherein R15 and R16 are independently selected from the group consisting of lower alkyl, and lower aralkyl, or together R15 and R16 are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S. Also more preferred are compounds wherein R15 and R16 are independently selected from the group consisting of C1-C6 alkyl, or together R15 and R16 are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S. In one aspect, particularly preferred are compounds wherein xe2x80x94NR15R16 is a cyclic amine. Especially preferred are such compounds wherein xe2x80x94NR15R16 is selected from the group consisting of morpholinyl and pyrrolidinyl.
Preferred are compounds R16 is xe2x80x94(CR12R13)nxe2x80x94C(O)xe2x80x94R14.
More preferred are compounds where n is 1, and wherein
R18 is selected from the group consisting of xe2x80x94H, methyl, and ethyl;
R12 and R13 are independently selected from the group consisting of xe2x80x94H, methyl, i-propyl, i-butyl, and benzyl, or together are connected via 2-5 carbon atoms to form a cycloalkyl group;
R14 is xe2x80x94OR17;
R17 is selected from the group consisting of methyl, ethyl, propyl, t-butyl, and benzyl; and
R15 and R16 are independently selected from the group consisting of lower alkyl, and lower aralkyl, or together R15 and R16 are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, and N. Particularly preferred are such compounds that are of the formula: 
More preferred are such compounds wherein n is 1. Especially preferred are such compounds wherein when R12 and R13 are not the same, then H2Nxe2x80x94CR12R13xe2x80x94C(O)xe2x80x94R14 is an ester, or thioester of a naturally occurring amino acid; and R14 is selected from the group consisting of xe2x80x94OR17 and xe2x80x94SR17.
In one aspect, preferred are compounds of formula IA or formula I wherein M is 
wherein:
A, E, and L are selected from the group consisting of xe2x80x94NR82, xe2x80x94NO2, xe2x80x94H, xe2x80x94OR, xe2x80x94SR7, xe2x80x94C(O)NR42, halo, xe2x80x94COR11, xe2x80x94SO2R3, guanidine, amidine, xe2x80x94NHSO2R5, xe2x80x94SO2NR42, xe2x80x94CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together A and L form a cyclic group, or together L and E form a cyclic group, or together E and J form a cyclic group including aryl, cyclic alkyl, and heterocyclic;
J is selected from the group consisting of xe2x80x94NR82, xe2x80x94NO2, xe2x80x94H, xe2x80x94OR7, xe2x80x94SR7, xe2x80x94C(O)NR42, halo, xe2x80x94C(O)R11, xe2x80x94CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl, and aralkyl, or together with Y forms a cyclic group including aryl, cyclic alkyl and heterocyclic alkyl;
X3 is selected from the group consisting of -alkyl(hydroxy)-, -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, - 1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X3 is not substituted with xe2x80x94COOR2, xe2x80x94SO3H, or xe2x80x94PO3R22;
xe2x80x94Y3 is selected from the group consisting of xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, xe2x80x94C(O)R3, xe2x80x94S(O)2R3, xe2x80x94C(O)xe2x80x94R11, xe2x80x94CONHR3, xe2x80x94NR22, and xe2x80x94OR , all except H are optionally substituted;
R2 is selected from the group consisting of R3 and xe2x80x94H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
each R4 is independently selected from the group consisting of xe2x80x94H, and alkyl, or together R4 and R4 form a cyclic alkyl group;
R5 is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic;
R7 is independently selected from the group consisting of xe2x80x94H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and xe2x80x94C(O)R10;
R8 is independently selected from the group consisting of xe2x80x94H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, xe2x80x94C(O)R10, or together they form a bidendate alkyl;
each R9 is independently selected from the group consisting of xe2x80x94H, alkyl, aralkyl, and alicyclic, or together R9 and R9 form a cyclic alkyl group;
R10 is selected from the group consisting of xe2x80x94H, lower alkyl, xe2x80x94NH2, lower aryl, and lower perhaloalkyl;
R11 is selected from the group consisting of alkyl, aryl, xe2x80x94NR22, and xe2x80x94OR2; and pharmaceutically acceptable prodrugs and salts thereof; with the provisos that:
a) when X3 is alkyl or alkene, then A is xe2x80x94N(R82);
b) X3 is not alkylamine and alkylaminoalkyl substituted with phosphonic esters and acids; and
c) A, L, E, J, and Y3 together may only form 0-2 cyclic groups.
More preferred are such compounds wherein X3 is not -alkoxyalkyl-, -alkyloxy-, alkythioalkyl-, and -alkylthio-. Particularly preferred are such compounds with the additional proviso that when X3 is aryl or alkylaryl, said aryl or alkylaryl group is not linked 1,4 through a six-membered aromatic ring.
Especially preferred benzimidazole compounds include those wherein A, L, and E are independently selected from the group consisting of xe2x80x94H, xe2x80x94NR82, xe2x80x94NO2, hydroxy, halogen, xe2x80x94OR7, alkylaminocarbonyl, xe2x80x94SR7, lower perhaloalkyl, and C1-C5 alkyl, or together E and J together form a cyclic group; and wherein J is selected from the group consisting of xe2x80x94H, halogen, lower alkyl, lower hydroxyalkyl, xe2x80x94NR82, lower R82N-alkyl, lower haloalkyl, lower perhaloalkyl, lower alkenyl, lower alkynyl, lower aryl, heterocyclic, and alicyclic; and wherein Y is selected from the group consisting of alicyclic and lower alkyl; wherein X3 is selected from the group consisting of -heteroaryl-, -alkylcarbonylamino-, -alkylaminocarbonyl-, and -alkoxycarbonyl-. More preferred are such compounds wherein
R18 is selected from the group consisting of xe2x80x94H, methyl, and ethyl;
R12 and R13 are independently selected from the group consisting of xe2x80x94H, methyl, i-propyl, i-butyl, and benzyl, or together are connected via 2-5 carbon atoms to form a cycloalkyl group;
R14 is xe2x80x94OR17;
R17 is selected from the group consisting of methyl, ethyl, propyl, t-butyl, and benzyl; and
R15 and R16 are independently selected from the group consisting of lower alkyl, and lower aralkyl, or together R15 and R16 are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, and N. Most preferred are such compounds wherein A is selected from the group consisting of xe2x80x94H, xe2x80x94NH2, xe2x80x94F, and xe2x80x94CH3;
L is selected from the group consisting of xe2x80x94H, xe2x80x94F, xe2x80x94OCH3, Cl and xe2x80x94CH3;
E is selected from the group consisting of xe2x80x94H, and xe2x80x94Cl;
J is selected from the group consisting of xe2x80x94H, halo, C1-C5 hydroxyalkyl, C1-C5 haloalkyl, C1-C5 R82N-alkyl, C1-C5 alicyclic, and C1-C5 alkyl;
X3 is selected from the group consisting of xe2x80x94CH2OCH2xe2x80x94, -methyleneoxycarbonyl-, and -furan-2,5-diyl-; and
Y is lower alkyl.
Also more preferred are such benzimidazoles where A is xe2x80x94NH2, L is xe2x80x94F, E is xe2x80x94H, J is ethyl, Y is isobutyl, and X3 is -furan-2,5-diyl-; or
where A is xe2x80x94NH2, L is xe2x80x94F, E is xe2x80x94H, J is N,N-dimethylaminopropyl, Y is isobutyl, and X3 is -furan-2,5-diyl-.
Particularly preferred are those compounds wherein 
is selected from the group consisting of 
wherein C* has S stereochemistry.
Preferably, oral bioavailability is at least 5%. More preferably, oral bioavailability is at least 10%.
The prodrugs of formula IA may have two isomeric forms around the phosphorus. Preferred is when the phosphorus is not chiral. Also preferred is when there is no chiral center in the amino groups attached to the phosphorus. Also preferred is when n is 1 and R12 is xe2x80x94H, then the carbon attached to R12 and R13 has S stereochemistry.
In another aspect preferred are compounds of formula I or Ixe2x80x94A where M is 
wherein
Zxe2x80x2 is selected from the group consisting of alkyl or halogen,
U and Vxe2x80x2 are independently selected from the group consisting of hydrogen, hydroxy, acyloxy or when taken together form a lower cyclic ring containing at least one oxygen;
Wxe2x80x2 is selected from the group consisting of amino and lower alkyl amino;
and pharmaceutically acceptable salts thereof
In another aspect, preferred are compounds of formula II 
wherein
A2 is selected from the group consisting of xe2x80x94NR82, NHSO2R3, xe2x80x94OR5, xe2x80x94SR5, halogen, lower alkyl, xe2x80x94CON(R4)2, guanidine, amidine, xe2x80x94H, and perhaloalkyl;
E2 is selected from the group consisting of xe2x80x94H, halogen, lower alkylthio, lower perhaloalkyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, xe2x80x94CN, and xe2x80x94NR72;
X3 is selected from the group consisting of -alkyl(hydroxy)-, -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X3 is not substituted with xe2x80x94COOR2, xe2x80x94SO3H, or xe2x80x94PO3R22;
Y3 is selected from the group consisting of xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, xe2x80x94C(O)R3, xe2x80x94S(O)2R3, xe2x80x94C(O)xe2x80x94R11, xe2x80x94CONHR3, xe2x80x94NR22, and xe2x80x94OR3, all except H are optionally substituted;
Y is independently selected from the group consisting of xe2x80x94Oxe2x80x94, and xe2x80x94NR6xe2x80x94;
when Y is xe2x80x94Oxe2x80x94, then R1 attached to xe2x80x94Oxe2x80x94 is independently selected from the group consisting of xe2x80x94H, alkyl, optionally substituted aryl, optionally substituted alicyclic where the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, xe2x80x94C(R2)2OC(O)NR22, xe2x80x94NR2xe2x80x94C(O)xe2x80x94R3, xe2x80x94C(R2)2xe2x80x94OC(O)R3, xe2x80x94C(R2)2xe2x80x94Oxe2x80x94C(O)OR3, xe2x80x94C(R2)2OC(O)SR3, -alkyl-Sxe2x80x94C(O)R3, -alkyl-Sxe2x80x94S-alkylhydroxy, and -alkyl-Sxe2x80x94Sxe2x80x94S-alkylhydroxy,
when Y is xe2x80x94NR6xe2x80x94, then R1 attached to xe2x80x94NR6xe2x80x94 is independently selected from the group consisting of xe2x80x94H, xe2x80x94[C(R2)2]qxe2x80x94COOR3, xe2x80x94C(R4)2COOR3, xe2x80x94[C(R2)2]qxe2x80x94C(O)SR, and -cycloalkylene-COOR3;
or when either Y is independently selected from xe2x80x94Oxe2x80x94 and xe2x80x94NR6xe2x80x94, then together R1 and R1 are -alkyl-Sxe2x80x94S-alkyl- to form a cyclic group, or together R1 and R1 are 
wherein
V, W, and Wxe2x80x2 are independently selected from the group consisting of xe2x80x94H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus;
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and Wxe2x80x2 are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
Z is selected from the group consisting of xe2x80x94CHR2OH, xe2x80x94CHR2OC(O)R3, xe2x80x94CHR2OC(S)R3, xe2x80x94CHR2OC(S)OR, xe2x80x94CHR2OC(O)SR3, xe2x80x94CHR2OCO2R3, xe2x80x94OR2, xe2x80x94SR2, xe2x80x94CHR2N3, xe2x80x94CH2aryl, xe2x80x94CH(aryl)OH, xe2x80x94CH(CHxe2x95x90CR22)OH, xe2x80x94CH(Cxe2x89xa1CR2)OH, xe2x80x94R2, xe2x80x94NR22, xe2x80x94OCOR3, xe2x80x94OCO2R3, xe2x80x94SCOR3, xe2x80x94SCO2R3, xe2x80x94NHCOR2, xe2x80x94NHCO2R3, xe2x80x94CH2NHaryl, xe2x80x94(CH2)pxe2x80x94OR2, and xe2x80x94(CH2)pxe2x80x94SR2;
p is an integer 2 or 3;
q is an integer 1 or 2;
with the provisos that:
a) V, Z, W, Wxe2x80x2 are not all xe2x80x94H; and
b) when Z is xe2x80x94R2 then at least one of V, W, and Wxe2x80x2 is not xe2x80x94H, alkyl, aralkyl, or alicyclic;
R2 is selected from the group consisting of R3 and xe2x80x94H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
each R4 is independently selected from the group consisting of xe2x80x94H, and alkyl, or together R4 and R4 form a cyclic alkyl group;
R6 is selected from the group consisting of xe2x80x94H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
R5 is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic;
R9 is independently selected from the group consisting of xe2x80x94H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and xe2x80x94(CO)R10;
R8 is independently selected from the group consisting of xe2x80x94H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, xe2x80x94C(O)R10, or together they form a bidendate alkyl;
R9 is selected from the group consisting of alkyl, aralkyl, and alicyclic;
R10 is selected from the group consisting of xe2x80x94H, lower alkyl, xe2x80x94NH2, lower aryl, and lower perhaloalkyl; and
R11 is selected from the group consisting of alkyl, aryl, xe2x80x94NR22, and xe2x80x94OR2; and pharmaceutically acceptable prodrugs and salts thereof.
Preferred A2 groups for formula II include xe2x80x94NR82, lower alkyl, lower perhaloalkyl, lower alkoxy, and halogen. Particularly preferred are xe2x80x94NR82, and halogen. Especially preferred is xe2x80x94NR82. Most preferred is xe2x80x94NH2.
Preferred E2 groups for formula II include xe2x80x94H, halogen, lower perhaloalkyl, xe2x80x94CN, lower alkyl, lower alkoxy, and lower alkylthio. Particularly preferred E2 groups include xe2x80x94H, xe2x80x94SMe, xe2x80x94Et, and xe2x80x94Cl. Especially preferred is xe2x80x94H and xe2x80x94SCH3.
Preferred X3 groups for formula II include -alkyl-, -alkynyl-, -alkoxyalkyl-, -alkylthio-, -aryl-, -1,1-dihaloalkyl-, -carbonylalkyl-, -heteroaryl-, -alkylcarbonylamino-, and -alkylaminocarbonyl. Particularly preferred is -alkyl- substituted with 1 to 3 substituents selected from halogen, and xe2x80x94OH. Particularly preferred are -alkylaminocarbonyl-, -alkoxyalkyl-, and -heteroaryl-. Preferred -alkoxyalkyl- groups include -methoxymethyl-. Preferred -heteroaryl- groups include -furan-2,5-diyl-, optionally substituted.
Preferred Y3 groups for formula II include aralkyl, alicyclic, alkyl, and aryl, all optionally substituted. Particularly preferred is lower alkyl. Particularly preferred Y3 groups include (2-naphthyl)methyl, cyclohexylethyl, phenylethyl, nonyl, cyclohexylpropyl, ethyl, cyclopropylmethyl, cyclobutylmethylphenyl, (2-methyl)propyl, neopentyl, cyclopropyl, cyclopentyl, (1-imidozolyl)propyl, 2-ethoxybenzyl, 1-hydroxy-2,2-dimethylpropyl, 1-chloro-2,2-dimethylpropyl, 2,2-dimethylbutyl, 2-(spiro-3,3-dimethylcyclohex-4-enyl)propyl, and 1-methylneopentyl. Especially preferred is neopentyl and isobutyl.
Preferred R4 and R7 groups are xe2x80x94H, and lower alkyl. Particularly preferred are xe2x80x94H, and methyl.
In another preferred aspect, A2 is xe2x80x94NR82 or halogen, E2 is xe2x80x94H, halogen, xe2x80x94CN, lower alkyl, lower perhaloalkyl, lower alkoxy, or lower alkylthio, X3 is -alkyl-, -alkoxyalkyl-, -alkynyl-, 1,1-dihaloalkyl-, -carbonylakyl-, -alkyl(OH)xe2x80x94, -alkylcarbonylamino-, -alkylaminocarbonyl-, -alkylthio-, -aryl-, or -heteroaryl-, and R4 and R7 is xe2x80x94H or lower alkyl. Particularly preferred are such compounds where Y3 is aralkyl, aryl, alicyclic, or alkyl.
In another preferred aspect, A2 is xe2x80x94NR82, E2 is xe2x80x94H, Clxe2x80x94, or methylthio, and X3 is optionally substituted -furan-2,5-diyl-, or -alkoxyalkyl-. Particularly preferred are such compounds where A2 is xe2x80x94NH2, X3 is -furan-2,5-diyl-, or -methoxymethyl-, and Y3 is lower alkyl. Most preferred are such compounds where E2 is H, X3 is -furan-2,5-diyl-, and Y3 is neopentyl; those where E2 is xe2x80x94SCH3, X3 is -furan-2,5-diyl-, and Y3 is isobutyl; and those where E2 is xe2x80x94H, X3 is -furan-2,5-diyl-, and Y3 is 1-(3-chloro-2,2-dimethyl)-propyl. Especially preferred are such compounds where R1 is xe2x80x94CH2Oxe2x80x94C(O)xe2x80x94C(CH3)3.
In another aspect, preferred are compounds of formula III 
wherein:
A, E, and L are selected from the group consisting of xe2x80x94NR82, xe2x80x94NO2, xe2x80x94H, xe2x80x94OR, xe2x80x94SR7, xe2x80x94C(O)NR42, halo, xe2x80x94COR11, xe2x80x94SO2R3, guanidine, amidine, xe2x80x94NHSO2R5, xe2x80x94SO2NR42, xe2x80x94CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together A and L form a cyclic group, or together L and E form a cyclic group, or together E and J form a cyclic group including aryl, cyclic alkyl, and heterocyclic;
J is selected from the group consisting of xe2x80x94NR82, xe2x80x94NO2, xe2x80x94H, xe2x80x94OR7, xe2x80x94SR7, xe2x80x94C(O)NR42, halo, xe2x80x94C(O)R11, xe2x80x94CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl, and aralkyl, or together with Y forms a cyclic group including aryl, cyclic alkyl and heterocyclic alkyl;
X3 is selected from the group consisting of -alkyl(hydroxy)-, -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X3 is not substituted with xe2x80x94COOR2, xe2x80x94SO3H, or xe2x80x94PO3RR22;
Y3 is selected from the group consisting of xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, xe2x80x94C(O)R3, xe2x80x94S(O)2R3, xe2x80x94C(O)xe2x80x94R11, xe2x80x94CONHR3, xe2x80x94NR22, and xe2x80x94OR3, all except H are optionally substituted;
Y is independently selected from the group consisting of xe2x80x94Oxe2x80x94, and xe2x80x94NR6xe2x80x94;
when Y is xe2x80x94Oxe2x80x94, then R1 attached to xe2x80x94Oxe2x80x94 is independently selected from the group consisting of xe2x80x94H, alkyl, optionally substituted aryl, optionally substituted alicyclic where the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, xe2x80x94C(R2)2OC(O)NR22, xe2x80x94NR2xe2x80x94C(O)xe2x80x94R3, xe2x80x94C(R2)2xe2x80x94OC(O)R3, xe2x80x94C(R2)2xe2x80x94Oxe2x80x94C(O)OR3, xe2x80x94C(R2)2OC(O)SR3, -alkyl-Sxe2x80x94C(O)R3, -alkyl-Sxe2x80x94S-alkylhydroxy, and -alkyl-Sxe2x80x94Sxe2x80x94S-alkylhydroxy,
when Y is xe2x80x94NR6xe2x80x94, then R1 attached to xe2x80x94NR6xe2x80x94 is independently selected from the group consisting of xe2x80x94H, xe2x80x94[C(R2)2]qxe2x80x94COOR3, xe2x80x94C(R4)2COOR3, xe2x80x94[C(R2)2]qxe2x80x94C(O)SR and -cycloalkylene-COOR3;
or when either Y is independently selected from xe2x80x94Oxe2x80x94 and xe2x80x94NR6xe2x80x94, then together R1 and R1 are -alkyl-Sxe2x80x94S-alkyl- to form a cyclic group, or together R1 and R1 are 
wherein
V, W, and Wxe2x80x2 are independently selected from the group consisting of xe2x80x94H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus;
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and Wxe2x80x2 are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
Z is selected from the group consisting of xe2x80x94CHR2OH, xe2x80x94CHR2OC(O)R3, xe2x80x94CHR2OC(S)R3, xe2x80x94CHR2OC(S)OR3, xe2x80x94CHR2OC(O)SR3, xe2x80x94CHR2OCO2R3, xe2x80x94OR2, xe2x80x94SR2, xe2x80x94CHR2N3, xe2x80x94CH2aryl, xe2x80x94CH(aryl)OH, xe2x80x94CH(CHxe2x95x90CR22)OH, xe2x80x94CH(Cxe2x89xa1CR2)OH, xe2x80x94R2, xe2x80x94NR22, xe2x80x94OCOR3, xe2x80x94OCO2R3, xe2x80x94SCOR3, xe2x80x94SCO2R3, xe2x80x94NHCOR2, xe2x80x94NHCO2R3, xe2x80x94CH2NHaryl, xe2x80x94(CH2)pxe2x80x94OR2, and xe2x80x94(CH2)pxe2x80x94SR2;
p is an integer 2 or 3;
q is an integer 1 or 2;
with the provisos that:
a) V, Z, W, Wxe2x80x2 are not all xe2x80x94H; and
b) when Z is xe2x80x94R2, then at least one of V, W, and Wxe2x80x2 is not xe2x80x94H, alkyl, aralkyl, or alicyclic;
R2 is selected from the group consisting of R3 and xe2x80x94H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
each R4 is independently selected from the group consisting of xe2x80x94H, and alkyl, or together R4 and R4 form a cyclic alkyl group;
R6 is selected from the group consisting of xe2x80x94H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
R5 is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic;
R7 is independently selected from the group consisting of xe2x80x94H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and xe2x80x94C(O)R10;
R8 is independently selected from the group consisting of xe2x80x94H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, xe2x80x94C(O)R10, or together they form a bidendate alkyl;
R9 is selected from the group consisting of alkyl, aralkyl, and alicyclic;
R10 is selected from the group consisting of xe2x80x94H, lower alkyl, xe2x80x94NH2, lower aryl, and lower perhaloalkyl;
R11 is selected from the group consisting of alkyl, aryl, xe2x80x94NR22, and xe2x80x94OR2, and
pharmaceutically acceptable prodrugs and salts thereof
Preferred A, L, and E groups for formula III include xe2x80x94H, xe2x80x94NR82, xe2x80x94NO2, hydroxy, alkylaminocarbonyl, halogen, xe2x80x94OR7, xe2x80x94SR7, lower perhaloalkyl, and C1-C5 alkyl, or together E and J form a cyclic group. Such a cyclic group may be aromatic, cyclic alkyl, or heterocyclic alkyl, and may be optionally substituted. Suitable aromatic groups include thiazole. Particularly preferred A, L and E groups are xe2x80x94NR82, xe2x80x94H, hydroxy, halogen, lower alkoxy, lower perhaloalkyl, and lower alkyl.
Preferred A groups for formula III include, xe2x80x94NR82, xe2x80x94H, halogen, lower perhaloalkyl, and lower alkyl.
Preferred L and E groups for formula III include xe2x80x94H, lower alkoxy, lower alkyl, and halogen.
Preferred J groups for formula III include xe2x80x94H, halogen, lower alkyl, lower hydroxylalkyl, xe2x80x94NR82, lower R82N-alkyl, lower haloalkyl, lower perhaloalkyl, lower alkenyl, lower alkynyl, lower aryl, heterocyclic, and alicyclic, or together with Y forms a cyclic group. Such a cyclic group may be aromatic, cyclic alkyl, or heterocyclic, and may be optionally substituted. Particularly preferred J groups include xe2x80x94H, halogen, and lower alkyl, lower hydroxyalkyl, xe2x80x94NR82, lower R82N-alkyl, lower haloalkyl, lower alkenyl, alicyclic, and aryl. Especially preferred are alicyclic and lower alkyl.
Preferred X3 groups for formula III include -alkyl-, -alkynyl-, -aryl-, -alkoxyalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -1,1-dihaloalkyl-, -carbonylalkyl-, and -alkyl(OH)xe2x80x94. Particularly preferred is -heteroaryl-, -alkylaminocarbonyl-, -1,1-dihaloalkyl-, and -alkoxyalkyl-. Also particularly preferred are -heteroaryl-, -alkylaminocarbonyl-, and -alkoxyalkyl-. Especially preferred are -methylaminocarbonyl-, -methoxymethyl-, and -furan-2,5-diyl-.
In another preferred aspect, when X3 is aryl or alkylaryl, these groups are not linked 1,4 through a 6-membered aromatic ring.
Preferred Y3 groups for formula III include xe2x80x94H, alkyl, aralkyl, aryl, and alicyclic, all except xe2x80x94H may be optionally substituted. Particularly preferred are lower alkyl, and alicyclic.
Preferred R4 and R7 groups include xe2x80x94H, and lower alkyl.
In one preferred aspect of compounds of formula III, A, L, and E are independently xe2x80x94H, lower alkyl, hydroxy, halogen, lower alkoxy, lower perhaloalkyl, and xe2x80x94NR82; X3 is -aryl-, -alkoxyalkyl-, -alkyl-, -alkylthio-, -1,1-dihaloalkyl-, -carbonylalkyl-, -alkyl(hydroxy)-, -alkylaminocarbonyl-, and -alkylcarbonylamino-; and each R4 and R7 is independently xe2x80x94H, and lower alkyl. Particularly preferred are such compounds where A, L, and E are independently xe2x80x94H, lower alkyl, halogen, and xe2x80x94NR82; J is xe2x80x94H, halogen, haloalkyl, hydroxyalkyl, R82N-alkyl, lower alkyl, lower aryl, heterocyclic, and alicyclic, or together with Y3 forms a cyclic group; and X3 is -heteroaryl-, -alkylaminocarbonyl-, -1,1-dihaloalkyl-, and -alkoxyalkyl-. Especially preferred are such compounds where A is xe2x80x94H, xe2x80x94NH2, xe2x80x94F, and xe2x80x94CH3, L is xe2x80x94H, xe2x80x94F, xe2x80x94OCH3, xe2x80x94Cl, and xe2x80x94CH3, E is xe2x80x94H and xe2x80x94Cl, J is xe2x80x94H, halo, C1-C5 hydroxyalkyl, C1-C5 haloalkyl, C1-C5 R82N-alkyl, C1-C5 alicyclic, and C1-C5 alkyl, X3 is xe2x80x94CH2OCH2xe2x80x94, and -furan-2,5-diyl-, and Y3 is lower alkyl. Most preferred are the following such compounds and their salts, and prodrug and their salts:
1) A is xe2x80x94NH2, L is xe2x80x94F, E is xe2x80x94H, J is xe2x80x94H, Y3 is isobutyl, and X3 is -furan-2,5-diyl-;
2) A, L, and J are xe2x80x94H, E is xe2x80x94Cl, Y3 is isobutyl, and X3 is -furan-2,5-diyl-;
3) A is xe2x80x94NH2, L is xe2x80x94F, E and J are xe2x80x94H, Y3 is cyclopropylmethyl, and X3 is -furan-2,5-diyl-;
4) A is xe2x80x94NH2, L is xe2x80x94F, E is xe2x80x94H, J is ethyl, Y3 is isobutyl, and X3 is -furan-2,5-diyl-;
5) A is xe2x80x94CH3, L is xe2x80x94Cl, E and J are xe2x80x94H, Y3 is isobutyl, and X3 is -furan-2,5-diyl-;
6) A is xe2x80x94NH2, L is xe2x80x94F, E is xe2x80x94H, J is xe2x80x94Cl, Y3 is isobutyl, and X3 is -furan-2,5-diyl-;
7) A is xe2x80x94NH2, L is xe2x80x94F, E is xe2x80x94H, J is xe2x80x94Br, Y3 is isobutyl, and X3 is xe2x80x94CH2OCH2xe2x80x94; and
8) A, L, E, and J are xe2x80x94CH3, Y3 is cyclopropylmethyl, and X3 is -furan-2,5-diyl-.
Also especially preferred are compounds where A is xe2x80x94NH2, L is xe2x80x94F, E is xe2x80x94H, J is bromopropyl, bromobutyl, chlorobutyl, cyclopropyl, hydroxypropyl, or N,N-dimethylaminopropyl, and X3 is -furan-2,5-diyl-. The preferred prodrug is where R1 is pivaloyloxymethyl or its HCl salt.
In another aspect, preferred are compounds of formula IV 
wherein:
B is selected from the group consisting of xe2x80x94NHxe2x80x94, xe2x80x94Nxe2x95x90 and xe2x80x94CHxe2x95x90;
D is selected from the group consisting of xe2x80x94Cxe2x95x90 and xe2x80x94Nxe2x80x94;
Q is selected from the group consisting of 
and 
with the proviso that when B is xe2x80x94NHxe2x80x94 then Q is xe2x80x94Cxe2x95x90 and D is 
when B is xe2x80x94CHxe2x95x90 then Q is xe2x80x94Nxe2x80x94 and D is 
when B is xe2x80x94Nxe2x95x90, then D is 
and Q is xe2x80x94Cxe2x95x90;
A, E, and L are selected from the group consisting of xe2x80x94NR82, xe2x80x94NO2, xe2x80x94H, xe2x80x94OR1, xe2x80x94SR1, xe2x80x94C(O)NR42, halo, xe2x80x94COR11, xe2x80x94SO2R3, guanidino, amidino, xe2x80x94NHSO2R5, xe2x80x94SO2NR42, xe2x80x94CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together A and L form a cyclic group, or together L and E form a cyclic group, or together E and J form a cyclic group including aryl, cyclic alkyl, and heterocyclic;
J is selected from the group consisting of xe2x80x94NR82, xe2x80x94NO2, xe2x80x94H, xe2x80x94OR7, xe2x80x94SR7, xe2x80x94C(O)NR42, halo, xe2x80x94C(O)R11, xe2x80x94CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl, and aralkyl, or together with Y forms a cyclic group including aryl, cyclic alkyl and heterocyclic alkyl;
X3 is selected from the group consisting of -alkyl(hydroxy)-, -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X3 is not substituted with xe2x80x94COOR2, xe2x80x94SO3H, or xe2x80x94PO3R22;
Y3 is selected from the group consisting of xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, xe2x80x94C(O)R3, xe2x80x94S(O)2R3, xe2x80x94C(O)xe2x80x94R11, xe2x80x94CONHR3, xe2x80x94NR22, and xe2x80x94OR3, all except H are optionally substituted;
Y is independently selected from the group consisting of xe2x80x94Oxe2x80x94, and xe2x80x94NR6xe2x80x94;
when Y is xe2x80x94Oxe2x80x94, then R1 attached to xe2x80x94Oxe2x80x94 is independently selected from the group consisting of xe2x80x94H, alkyl, optionally substituted aryl, optionally substituted alicyclic where the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, xe2x80x94C(R2)2OC(O)NR22, xe2x80x94NR2xe2x80x94C(O)xe2x80x94R3, xe2x80x94C(R2)2xe2x80x94OC(O)R3, xe2x80x94C(R2)2xe2x80x94Oxe2x80x94C(O)OR3, xe2x80x94C(R2)2OC(O)SR3, -alkyl-Sxe2x80x94C(O)R3, -alkyl-Sxe2x80x94S-alkylhydroxy, and -alkyl-Sxe2x80x94Sxe2x80x94S-alkylhydroxy,
when Y is xe2x80x94NR6xe2x80x94, then R1 attached to xe2x80x94NR6xe2x80x94 is independently selected from the group consisting of xe2x80x94H, xe2x80x94[C(R2)2]qxe2x80x94COOR3, xe2x80x94C(R4)2COOR3, xe2x80x94[C(R2)2]qxe2x80x94C(O)SR and -cycloalkylene-COOR3;
or when either Y is independently selected from xe2x80x94Oxe2x80x94 and xe2x80x94NR6xe2x80x94, then together R1 and R1 are -alkyl-Sxe2x80x94S-alkyl- to form a cyclic group, or together R1 and R1 are 
wherein
V, W, and Wxe2x80x2 are independently selected from the group consisting of xe2x80x94H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus;
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and Wxe2x80x2 are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
Z is selected from the group consisting of xe2x80x94CHR2OH, xe2x80x94CHR2OC(O)R3, xe2x80x94CHR2OC(S)R3, xe2x80x94CHR2OC(S)OR3, xe2x80x94CHR2OC(O)SR3, xe2x80x94CHR2OCO2R3, xe2x80x94OR2, xe2x80x94SR2, xe2x80x94CHR2N3, xe2x80x94CH2aryl, xe2x80x94CH(aryl)OH, xe2x80x94CH(CHxe2x95x90CR22)OH, xe2x80x94CH(Cxe2x89xa1CR2)OH, xe2x80x94R2, xe2x80x94NR22, xe2x80x94OCOR3, xe2x80x94OCO2R3, xe2x80x94SCOR3, xe2x80x94SCO2R3, xe2x80x94NHCOR2, xe2x80x94NHCO2R3, xe2x80x94CH2NHaryl, xe2x80x94(CH2)pxe2x80x94OR2, and xe2x80x94(CH2)pxe2x80x94SR2;
p is an integer 2 or 3;
q is an integer 1 or 2;
with the provisos that:
a) V, Z, W, Wxe2x80x2 are not all xe2x80x94H; and
b) when Z is xe2x80x94R2, then at least one of V, W, and Wxe2x80x2 is not xe2x80x94H, alkyl, aralkyl, or alicyclic;
R2 is selected from the group consisting of R3 and xe2x80x94H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
each R4 is independently selected from the group consisting of xe2x80x94H, and alkyl, or together R4 and R4 form a cyclic alkyl group;
R6 is selected from the group consisting of xe2x80x94H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
R5 is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic;
R7 is independently selected from the group consisting of xe2x80x94H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and xe2x80x94C(O)R10;
R8 is independently selected from the group consisting of xe2x80x94H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, xe2x80x94C(O)R10, or together they form a bidentate alkyl;
R9 is selected from the group consisting of alkyl, aralkyl, and alicyclic;
R10 is selected from the group consisting of xe2x80x94H, lower alkyl, xe2x80x94NH2, lower aryl, and lower perhaloalkyl;
R11 is selected from the group consisting of alkyl, aryl, xe2x80x94NR22 and xe2x80x94OR2; and
pharmaceutically acceptable prodrugs and salts thereof.
Preferred A, L, and E groups in formula IV include xe2x80x94H, xe2x80x94NR82, xe2x80x94NO2, hydroxy, halogen, xe2x80x94OR7, alkylaminocarbonyl, xe2x80x94SR7, lower perhaloalkyl, and C1-C5 alkyl, or together E and J form a cyclic group. Such a cyclic group may be aromatic or cyclic alkyl, and may be optionally substituted. Suitable aromatic groups include thiazole. Particularly preferred A, L and E groups are xe2x80x94NR82, xe2x80x94H, hydroxy, halogen, lower alkoxy, lower perhaloalkyl, and lower alkyl.
Preferred A groups in formula IV include xe2x80x94NR82, lower alkyl, xe2x80x94H, halogen, and lower perhaloalkyl.
Preferred L and E groups in formula IV include xe2x80x94H, lower alkoxy, lower alkyl, and halogen.
Preferred J groups in formula IV include xe2x80x94H, halogen, lower alkyl, lower hydroxyalkyl, xe2x80x94NR82, lower R82N-alkyl, lower haloalkyl, lower perhaloalkyl, lower alkenyl, lower alkynyl, lower aryl, heterocyclic, and alicyclic or together with Y3 forms a cyclic group. Such a cyclic group may be aromatic or cyclic alkyl, and may be optionally substituted. Particularly preferred J groups xe2x80x94H, halogen, lower alkyl, lower hydroxyalkyl, xe2x80x94NR82, lower R82N-alkyl, lower haloalkyl, lower alkenyl, alicyclic, and aryl.
Preferred X3 groups in formula IV include -alkyl-, -alkynyl-, -alkoxyalkyl-, -alkylthio-, -aryl-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -1,1-dihaloalkyl-, -carbonylalkyl-, and -alkyl(OH)xe2x80x94. Particularly preferred is -1,1-dihaloalkyl-, -alkylaminocarbonyl-, -alkoxyalkyl-, and -heteroaryl-. Such compounds that are especially preferred are -heteroaryl-, -alkylaminocarbonyl-, and -alkoxyalkyl-. Most preferred is -methylaminocarbonyl-, -methoxymethyl-, and -furan-2,5-diyl.
In one preferred aspect, X3 is not -(C2-C3 alkyl)aminocarbonyl-.
Preferred Y3 groups for formula IV include xe2x80x94H, alkyl, aryl, aralkyl, and alicyclic, all except xe2x80x94H may be optionally substituted. Particularly preferred Y3 groups include lower alkyl, and alicyclic.
Preferred R4 and R7 groups include xe2x80x94H, and lower alkyl.
In one preferred aspect of formula IV, B is NH, D is 
and Q is xe2x80x94Cxe2x95x90. In another preferred aspect, B is xe2x80x94Nxe2x95x90, D is 
and Q is xe2x80x94Cxe2x95x90.
In another preferred aspect of formula IV, A, L, and E are independently xe2x80x94NR82, lower alkyl, lower perhaloalkyl, lower alkoxy, halogen, xe2x80x94OH, or xe2x80x94H, X3 is -aryl-, -alkoxyalkyl-, -alkyl-, -alkylthio-, -1,1-dihaloalkyl-, -carbonylalkyl-, -alkyl(hydroxy)-, -alkylaminocarbonyl-, and -alkylcarbonylamino-, and each R4 and R7 is independently xe2x80x94H, or lower alkyl. Particularly preferred are such compounds where A, L, and E are independently xe2x80x94H, lower alkyl, halogen, and xe2x80x94NR82; J is xe2x80x94H, halogen, haloalkyl, hydroxyalkyl, xe2x80x94R82N-alkyl, lower alkyl, lower aryl, heterocyclic, and alicyclic, or together with Y3 forms a cyclic group; and X3 is -heteroaryl-, -alkylaminocarbonyl-, -1,1-dihaloalkyl-, and -alkoxyalkyl-. Especially preferred are such compounds where A is xe2x80x94H, xe2x80x94NH2, xe2x80x94F, or xe2x80x94CH3, L is xe2x80x94H, xe2x80x94F, xe2x80x94OCH3, or xe2x80x94CH3, E is xe2x80x94H, or xe2x80x94Cl, J is xe2x80x94H, halo, C1-C5 hydroxyalkyl, C1-C5 haloalkyl, C1-C5 R82N-alkyl, C1-C5 alicyclic or C1-C5 alkyl, X3 is xe2x80x94CH2OCH2xe2x80x94, or -furan-2,5-diyl-; and Y3 is lower alkyl. Preferred are such compounds where
B is NH, D is 
and Q is xe2x80x94Cxe2x95x90 or where B is xe2x80x94Nxe2x95x90, D is 
and Q is xe2x80x94Cxe2x95x90.
Most preferred are compounds where:
1) A is xe2x80x94NH2, L is xe2x80x94F, E is xe2x80x94H, J is xe2x80x94H, Y3 is isobutyl, and X3 is -furan-2,5-diyl-;
2) A is xe2x80x94NH2, L is xe2x80x94F, E is xe2x80x94H, J is xe2x80x94Cl, Y3 is isobutyl, and X3 is -furan-2,5-diyl-.
3) A is xe2x80x94H, L is xe2x80x94H, E is xe2x80x94Cl, J is xe2x80x94H, B is xe2x80x94NH, D is 
Q is xe2x80x94Cxe2x95x90, and Y3 is isobutyl; and
4) A is xe2x80x94CH3, L is xe2x80x94H, E is xe2x80x94H, J is xe2x80x94H, B is xe2x80x94Nxe2x95x90, D is 
Q is xe2x80x94Cxe2x95x90, and Y3 is isobutyl.
Particularly preferred are such compounds where R1 is xe2x80x94CH2OC(O)xe2x80x94C(CH3)3.
Another especially preferred aspect are such compounds where A, L, and E are xe2x80x94H, lower alkyl, halogen, or xe2x80x94NR82, J is xe2x80x94H, halogen, lower alkyl, lower aryl, heterocyclic, or alicyclic, or together with Y3 forms a cyclic group, and X3 is -heteroaryl-, -alkylaminocarbonyl-, or -alkoxyalkyl-.
In another aspect, preferred are compounds of formula V wherein M is R5xe2x80x94Xxe2x80x94
wherein
R5 is selected from the group consisting of: 
wherein:
each G is independently selected from the group consisting of C, N, O, S, and Se, and wherein only one G may be O, S, or Se, and at most one G is N;
each Gxe2x80x2 is independently selected from the group consisting of C and N and wherein no more than two Gxe2x80x2 groups are N;
A is selected from the group consisting of xe2x80x94H, xe2x80x94NR42, xe2x80x94CONR42, xe2x80x94CO2R3, halo, xe2x80x94S(O)R3, xe2x80x94SO2R3, alkyl, alkenyl, alkynyl, perhaloalkyl, haloalkyl, aryl, xe2x80x94CH2OH, xe2x80x94CH2NR42, xe2x80x94CH2CN, xe2x80x94CN, xe2x80x94C(S)NH2, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94N3, xe2x80x94NHC(S)NR42, xe2x80x94NHAc, and null;
each B and D are independently selected from the group consisting of xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, alkoxyalkyl, xe2x80x94C(O)R11, xe2x80x94C(O)SR3, xe2x80x94SO2R11, xe2x80x94S(O)R3, xe2x80x94CN, xe2x80x94NR92, xe2x80x94OR3, xe2x80x94SR3, perhaloalkyl, halo, xe2x80x94NO2, and null, all except xe2x80x94H, xe2x80x94CN, perhaloalkyl, xe2x80x94NO2, and halo are optionally substituted;
E is selected from the group consisting of xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, xe2x80x94C(O)OR3, xe2x80x94CONR42, xe2x80x94CN, xe2x80x94NR92, xe2x80x94NO2, xe2x80x94OR3, xe2x80x94SR3, perhaloalkyl, halo, and null, all except xe2x80x94H, xe2x80x94CN, perhaloalkyl, and halo are optionally substituted;
J is selected from the group consisting of xe2x80x94H and null;
X is an optionally substituted linking group that links R5 to the phosphorus atom via 2-4 atoms, including 0-1 heteroatoms selected from N, O, and S, except that if X is urea or carbamate there is 2 heteroatoms, measured by the shortest path between R5 and the phosphorus atom, and wherein the atom attached to the phosphorus is a carbon atom, and wherein X is selected from the group consisting of -alkyl(hydroxy)-, -alkynyl-, -heteroaryl-, -carbonylalkyl-, 1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X is not substituted with xe2x80x94COOR2, xe2x80x94SO3H, or xe2x80x94PO3R22;
R2 is selected from the group consisting of R3 and xe2x80x94H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
each R4 is independently selected from the group consisting of xe2x80x94H, and alkyl, or together R4 and R4 form a cyclic alkyl group;
each R9 is independently selected from the group consisting of xe2x80x94H, alkyl, aralkyl, and alicyclic, or together R9 and R9 form a cyclic alkyl group;
R11 is selected from the group consisting of alkyl, aryl, xe2x80x94NR22, and xe2x80x94OR2; and with the proviso that:
1) when Gxe2x80x2 is N, then the respective A, B, D, or E is null;
2) at least one of A and B, or A, B, D, and E is not selected from the group consisting of xe2x80x94H or null;
3) when R5 is a six-membered ring, then X is not any 2 atom linker, an optionally substituted -alkyloxy-, or an optionally substituted -alkylthio-;
4) when G is N, then the respective A or B is not halogen or a group directly bonded to G via a heteroatom;
5) when X is not a -heteroaryl- group, then R5 is not substituted with two or more aryl groups;
Y is independently selected from the group consisting of xe2x80x94Oxe2x80x94, and xe2x80x94NR6xe2x80x94;
when Y is xe2x80x94Oxe2x80x94, then R1 attached to xe2x80x94Oxe2x80x94 is independently selected from the group consisting of xe2x80x94H, alkyl, optionally substituted aryl, optionally substituted alicyclic where the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, xe2x80x94C(R2)2OC(O)NR22, xe2x80x94NR2xe2x80x94C(O)xe2x80x94R3, xe2x80x94C(R2)2xe2x80x94OC(O)R3, xe2x80x94C(R2)2xe2x80x94Oxe2x80x94C(O)OR3, xe2x80x94C(R2)2OC(O)SR3, -alkyl-Sxe2x80x94C(O)R3, -alkyl-Sxe2x80x94S-alkylhydroxy, and -alkyl-Sxe2x80x94Sxe2x80x94S-alkylhydroxy,
when Y is xe2x80x94NR6xe2x80x94, then R1 attached to xe2x80x94NR6xe2x80x94 is independently selected from the group consisting of xe2x80x94H, xe2x80x94[C(R2)2]qxe2x80x94COOR3, xe2x80x94C(R4)2COOR3, xe2x80x94[C(R2)2]qxe2x80x94C(O)SR, and -cycloalkylene-COOR3;
or when either Y is independently selected from xe2x80x94Oxe2x80x94 and xe2x80x94NR6xe2x80x94, then together R1 and R1 are -alkyl-Sxe2x80x94S-alkyl- to form a cyclic group, or together R1 and R1 are 
wherein
V, W, and Wxe2x80x2 are independently selected from the group consisting of xe2x80x94H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus;
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and Wxe2x80x2 are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
Z is selected from the group consisting of xe2x80x94CHR2OH, xe2x80x94CHR2OC(O)R3, xe2x80x94CHR2OC(S)R3, xe2x80x94CHR2OC(S)OR3, xe2x80x94CHR2OC(O)SR3, xe2x80x94CHR2OCO2R3, xe2x80x94OR2, xe2x80x94SR2, xe2x80x94CHR2N3, xe2x80x94CH2aryl, xe2x80x94CH(aryl)OH, xe2x80x94CH(CHxe2x95x90CR22)OH, xe2x80x94CH(Cxe2x89xa1CR2)OH, xe2x80x94R2, NR22, xe2x80x94OCOR3, xe2x80x94OCO2R3, xe2x80x94SCOR3, xe2x80x94SCO2R3, xe2x80x94NHCOR2, xe2x80x94NHCO2R3, xe2x80x94CH2NHaryl, xe2x80x94(CH2)pxe2x80x94OR2, and xe2x80x94(CH2)pxe2x80x94SR2;
p is an integer 2 or 3;
is an integer 1 or 2;
with the provisos that:
a) V, Z, W, Wxe2x80x2 are not all xe2x80x94H; and
b) when Z is xe2x80x94R2, then at least one of V, W, and Wxe2x80x2 is not xe2x80x94H, alkyl, aralkyl, or alicyclic;
R2 is selected from the group consisting of R3 and xe2x80x94H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
each R4 is independently selected from the group consisting of xe2x80x94H, and alkyl, or together R4 and R4 form a cyclic alkyl group;
R6 is selected from the group consisting of xe2x80x94H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
In one preferred aspect of formula V-1 and formula V-2 compounds,
Axe2x80x3 is selected from the group consisting of xe2x80x94NH2, xe2x80x94CONH2, halo, xe2x80x94CH3, xe2x80x94CF3, xe2x80x94CH2-halo, xe2x80x94CN, xe2x80x94OCH3, xe2x80x94SCH3, and xe2x80x94H;
Bxe2x80x3 is selected from the group consisting of xe2x80x94H, xe2x80x94C(O)R11, xe2x80x94C(O)SR3, alkyl, aryl, alicyclic, halo, xe2x80x94CN, xe2x80x94SR3, OR3 and xe2x80x94NR92;
Dxe2x80x3 is selected from the group consisting of xe2x80x94H, xe2x80x94C(O)R11, xe2x80x94C(O)SR3, xe2x80x94NR92, alkyl, aryl, alicyclic, halo, and xe2x80x94SR3;
Exe2x80x3 is selected from the group consisting of xe2x80x94H, C1-C6 alkyl, lower alicyclic, halo, xe2x80x94CN, xe2x80x94C(O)OR3, and xe2x80x94SR3.
X is selected from the group consisting of -alkyl(hydroxy)-, -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted;
when both Y groups are xe2x80x94Oxe2x80x94, then R1 is independently selected from the group consisting of optionally substituted aryl, optionally substituted benzyl, xe2x80x94C(R2)2OC(O)R3, xe2x80x94C(R2)2OC(O)OR3, and xe2x80x94H; or
when one Y is xe2x80x94Oxe2x80x94, then R1 attached to xe2x80x94Oxe2x80x94 is optionally substituted aryl; and the other Y is xe2x80x94NR6xe2x80x94, then R1 attached to xe2x80x94NR6xe2x80x94 is selected from the group consisting of xe2x80x94C(R4)2COOR3, and xe2x80x94C(R2)2COOR3; or
when Y is xe2x80x94Oxe2x80x94 or xe2x80x94NR6xe2x80x94, then together R1 and R1 are 
wherein
V, W, and Wxe2x80x2 are independently selected from the group consisting of xe2x80x94H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl, or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and Wxe2x80x2 are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
Z is selected from the group consisting of xe2x80x94CHR2OH, xe2x80x94CHR2OC(O)R3, xe2x80x94CHR2OC(S)R3, xe2x80x94CHR2OC(S)OR3, xe2x80x94CHR2OC(O)SR3, xe2x80x94CHR2OCO2R3, xe2x80x94OR2, xe2x80x94SR2, xe2x80x94R2, xe2x80x94NHCOR2, xe2x80x94NHCO2R3, xe2x80x94(CH2)pxe2x80x94OR2, and xe2x80x94(CH2)pxe2x80x94SR2;
with the provisos that:
a) V, Z, W, Wxe2x80x2 are not all xe2x80x94H;
b) when Z is xe2x80x94R2, then at least one of V, W, and Wxe2x80x2 is not xe2x80x94H, alkyl, aralkyl, or alicyclic; and
c) both Y groups are not xe2x80x94NR6xe2x80x94;
R2 is selected from the group consisting of R3 and xe2x80x94H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R6 is selected from the group consisting of xe2x80x94H, and lower alkyl.
In one particularly preferred aspect of formula I where M is R5xe2x80x94Xxe2x80x94 and R5 is 
X is selected from the group consisting of methylenoxycarbonyl, and furan-2,5-diyl; at least one Y group is xe2x80x94Oxe2x80x94; and pharmaceutically acceptable salts and prodrugs thereof. More preferred are such compounds wherein when Y is xe2x80x94Oxe2x80x94, then R1 attached to xe2x80x94Oxe2x80x94 is independently selected from the group consisting of xe2x80x94H, optionally substituted phenyl,
xe2x80x94CH2OC(O)-tBu, xe2x80x94CH2OC(O)Et and xe2x80x94CH2OC(O)-iPr;
when Y is xe2x80x94NR6xe2x80x94, then R1 is attached to xe2x80x94NR6xe2x80x94 independently selected from the group consisting of xe2x80x94C(R2)2COOR3, xe2x80x94C(R4)2COOR3, or
when Y is xe2x80x94Oxe2x80x94 or xe2x80x94NR6xe2x80x94, and at least one Y is xe2x80x94Oxe2x80x94, then together R1 and R1 are 
wherein
V is selected from the group consisting of optionally substituted aryl, and optionally substituted heteroaryl; and Z, Wxe2x80x2, and W are H; and
R6 is selected from the group consisting of xe2x80x94H, and lower alkyl.
The following such compounds and their salts are most preferred:
1) Axe2x80x3 is xe2x80x94NH2, X is furan-2,5-diyl, and Bxe2x80x3 is xe2x80x94CH2xe2x80x94CH(CH3)2;
2) Axe2x80x3 is xe2x80x94NH2, X is furan-2,5-diyl, and Bxe2x80x3 is xe2x80x94COOEt;
3) Axe2x80x3 is xe2x80x94NH2, X is furan-2,5-diyl, and Bxe2x80x3 is xe2x80x94SCH3;
4) Axe2x80x3 is xe2x80x94NH2, X is furan-2,5-diyl, and Bxe2x80x3 is xe2x80x94SCH2CH2SCH3;
5) Axe2x80x3 is xe2x80x94NH2, X is methyleneoxycarbonyl, and Bxe2x80x3 is xe2x80x94CH(CH3)2.
In another particularly preferred aspect of formula I where M is R5xe2x80x94Xxe2x80x94, R5 is 
X is furan-2,5-diyl, and methyleneoxycarbonyl, and Axe2x80x3 is xe2x80x94NH2; at least one Y group is xe2x80x94Oxe2x80x94; and pharmaceutically acceptable salts and prodrugs thereof. Especially preferred are such compounds wherein
when Y is xe2x80x94Oxe2x80x94, then each R1 is independently selected from the group consisting of xe2x80x94H, optionally substituted phenyl, xe2x80x94CH2OC(O)-tBu, xe2x80x94CH2OC(O)Et, and, xe2x80x94CH2OC(O)-iPr;
or when Y is xe2x80x94NR6xe2x80x94, then each R1 is independently selected from the group consisting of xe2x80x94C(R2)2C(O)OR3, and xe2x80x94C(R4)2COOR3;
or when Y is independently selected from xe2x80x94Oxe2x80x94 and xe2x80x94NR6xe2x80x94, then together R1 and R1 are 
wherein
V selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; and Z, Wxe2x80x2, and W are H. Also especially preferred are such compounds wherein Bxe2x80x3 is xe2x80x94SCH2CH2CH3.
In another particularly preferred aspect of formula I where M is R5xe2x80x94Xxe2x80x94 and R5 is 
Axe2x80x3 is xe2x80x94NH2, Exe2x80x3 and Dxe2x80x3 are xe2x80x94H, Bxe2x80x3 is n-propyl and cyclopropyl, X is furan-2,5-diyl and methyleneoxycarbonyl; at least one Y group is xe2x80x94Oxe2x80x94; and pharmaceutically acceptable salts and prodrugs thereof. Especially preferred are such compounds wherein R1 is selected from the group consisting of xe2x80x94H, optionally substituted phenyl xe2x80x94CH2OC(O)-tBu, xe2x80x94CH2OC(O)Et, and xe2x80x94CH2OC(O)-iPr,
or when Y is xe2x80x94NR6, then each R1 is independently selected from the group consisting of xe2x80x94C(R2)2C(O)OR3, and xe2x80x94C(R4)2COOR3;
or when either Y is independently selected from xe2x80x94Oxe2x80x94 and xe2x80x94NR6xe2x80x94, and at least one Y is xe2x80x94Oxe2x80x94, then together R1 and R1 are 
wherein
V is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; and Z, Wxe2x80x2, and W are H.
In another particularly preferred aspect of formula, I where M is R5xe2x80x94Xxe2x80x94 and R5 is 
Axe2x80x3 is xe2x80x94NH2, Dxe2x80x3 is xe2x80x94H, Bxe2x80x3 is n-propyl and cyclopropyl, X is furan-2,5-diyl and methyleneoxycarbonyl; at least one,Y group is xe2x80x94Oxe2x80x94; and pharmaceutically acceptable salts and prodrugs thereof. Especially preferred are such compounds wherein when Y is xe2x80x94Oxe2x80x94 then R1 is selected from the group consisting of xe2x80x94H, optionally substituted phenyl, xe2x80x94CH2OC(O)-tBu, xe2x80x94CH2OC(O)Et, and xe2x80x94CH2OC(O)-iPr;
or when one Y is xe2x80x94Oxe2x80x94 and its corresponding R1 is -phenyl while the other Y is xe2x80x94NHxe2x80x94 and its corresponding R1 is xe2x80x94CH(Me)C(O)OEt, or
when at least one Y group is xe2x80x94Oxe2x80x94, then together R1 and R1 are 
wherein
V is selected from the group, consisting of optionally substituted aryl and optionally substituted heteroaryl; and Z, Wxe2x80x2, and W are H.
Preferred are compounds of formula (X): 
wherein:
Gxe2x80x3 is selected from the group consisting of xe2x80x94Oxe2x80x94 and xe2x80x94Sxe2x80x94;
A2, L2, E2, and J2 are selected from the group consisting of xe2x80x94NR42, xe2x80x94NO2, xe2x80x94H, xe2x80x94OR2, xe2x80x94SR2, xe2x80x94C(O)NR42, halo, xe2x80x94COR11, xe2x80x94SO2R3, guanidinyl, amidinyl, aryl, aralkyl, alkyoxyalkyl, xe2x80x94SCN, xe2x80x94NHSO2R9, xe2x80x94SO2NR42, xe2x80x94CN, xe2x80x94S(O)R3, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together L2 and E2 or E2 and J2 form an annulated cyclic group;
X2 is selected from the group consisting of xe2x80x94CR2xe2x80x94, xe2x80x94CF2xe2x80x94, xe2x80x94OCR22xe2x80x94, xe2x80x94SCR22xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94Sxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(S)xe2x80x94, and xe2x80x94NR19CR22xe2x80x94, and wherein in the atom attached to the phosphorus is a carbon atom; with the proviso that X2 is not substituted with xe2x80x94COOR2, xe2x80x94SO3H, or xe2x80x94PO3R22;
R19 is selected from the group consisting of lower alkyl, xe2x80x94H, and xe2x80x94COR2; and
Y is independently selected from the group consisting of xe2x80x94Oxe2x80x94, and xe2x80x94NR6xe2x80x94;
when Y is xe2x80x94Oxe2x80x94, then R1 attached to xe2x80x94Oxe2x80x94 is independently selected from the group consisting of xe2x80x94H, alkyl, optionally substituted aryl, optionally substituted alicyclic where the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, xe2x80x94C(R2)2OC(O)NR22, xe2x80x94NR2xe2x80x94C(O)xe2x80x94R3, xe2x80x94C(R2)2xe2x80x94OC(O)R3, xe2x80x94C(R2)2xe2x80x94Oxe2x80x94C(O)OR3, xe2x80x94C(R2)2OC(O)SR3, -alkyl-Sxe2x80x94C(O)R3, -alkyl-Sxe2x80x94S-alkylhydroxy, and -alkyl-Sxe2x80x94Sxe2x80x94S-alkylhydroxy,
when Y is xe2x80x94NR6xe2x80x94, then R1 attached to xe2x80x94NR6xe2x80x94 is independently selected from the group consisting of xe2x80x94H, xe2x80x94[C(R2)2]qxe2x80x94COOR3, xe2x80x94C(R4)2COOR3, xe2x80x94[C(R2)2]qxe2x80x94C(O)SR, and -cycloalkylene-COOR3;
or when either Y is independently selected from xe2x80x94Oxe2x80x94 and xe2x80x94NR6xe2x80x94, then together R1 and R1 are -alkyl-Sxe2x80x94S-alkyl- to form a cyclic group, or together R1 and R1 are 
wherein
V, W, and Wxe2x80x2 are independently selected from the group consisting of xe2x80x94H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus;
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and Wxe2x80x2 are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
Z is selected from the group consisting of xe2x80x94CHR2OH, xe2x80x94CHR2OC(O)R3, xe2x80x94CHR2OC(S)R3, xe2x80x94CHR2OC(S)OR3, xe2x80x94CHR2OC(O)SR3, xe2x80x94CHR2OCO2R3, xe2x80x94OR2, xe2x80x94SR2, xe2x80x94CHR2N3, xe2x80x94CH2aryl, xe2x80x94CH(aryl)OH, xe2x80x94CH(CHxe2x95x90CR22)OH, xe2x80x94CH(Cxe2x89xa1CR2)OH, xe2x80x94R2, xe2x80x94NR22, xe2x80x94OCOR3, xe2x80x94OCO2R3, xe2x80x94SCOR3, xe2x80x94SCO2R3, xe2x80x94NHCOR2, xe2x80x94NHCO2R3, xe2x80x94CH2NHaryl, xe2x80x94(CH2)pxe2x80x94OR2, and xe2x80x94(CH2)pxe2x80x94SR2;
p is an integer 2 or 3;
q is an integer 1 or 2;
with the provisos that:
a) V, Z, W, Wxe2x80x2 are not all xe2x80x94H; and
b) when Z is xe2x80x94R2, then at least one of V, W, and Wxe2x80x2 is not xe2x80x94H, alkyl, aralkyl, or licyclic;
R2 is selected from the group consisting of R3 and xe2x80x94H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
each R4 is independently selected from the group consisting of xe2x80x94H, alkyl, or together R4 and R4 form a cyclic alkyl;
R6 is selected from the group consisting of xe2x80x94H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
each R9 is independently selected from the group consisting of xe2x80x94H, alkyl, aralkyl, and alicyclic, or together R9 and R9 form a cyclic alkyl group;
R11 is selected from the group consisting of alky, aryl, NR22, and xe2x80x94OR2; and pharmaceutically acceptable prodrugs and salts thereof
More preferred are compounds wherein Gxe2x80x3 is xe2x80x94Sxe2x80x94. Most preferred are compounds wherein A2, L2, E2, and J2 are independently selected from the group consisting of xe2x80x94H, xe2x80x94NR42, xe2x80x94Sxe2x80x94Cxe2x89xa1N, halogen, xe2x80x94OR3, hydroxy, -alkyl(OH), aryl, alkyloxycarbonyl, xe2x80x94SR3, lower perhaloalkyl, and C1-C5 alkyl, or together L2 and E2 form an annulated cyclic group. More preferably A2, L2, E2 and J2 are independently selected from the group consisting of xe2x80x94H, xe2x80x94NR42, xe2x80x94Sxe2x80x94Cxe2x89xa1N, halogen, lower alkoxy, hydroxy, lower alkyl(hydroxy), lower aryl, and C1-C5 alkyl, or together L2 and E2 form an annulated cyclic group.
Most preferred A2 groups include xe2x80x94NH2, xe2x80x94H, halo, and C1-C5 alkyl.
Most preferred L2 and E2 groups are those independently selected from the group consisting of xe2x80x94H, xe2x80x94Sxe2x80x94Cxe2x89xa1N, lower alkoxy, C1-C5 alkyl, lower alkyl(hydroxy), lower aryl, and halogen or together L2 and E2 form an annulated cyclic group containing an additional 4 carbon atoms.
Most preferred J2 groups include xe2x80x94H, and C1-C5 alkyl.
Preferred X2 groups include xe2x80x94CF2xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94OC(O)xe2x80x94 xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94NHCH2xe2x80x94, and xe2x80x94N(C(O)CH3)xe2x80x94CH2xe2x80x94. More preferred are xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, and xe2x80x94N(C(O)CH3)xe2x80x94CH2xe2x80x94. Most preferred is xe2x80x94OCH2xe2x80x94.
One preferred aspect include compound wherein A2 is selected from the group consisting of xe2x80x94H, xe2x80x94NH2, xe2x80x94CH3, xe2x80x94Cl, and xe2x80x94Br;
L2 is xe2x80x94H, lower alkyl, halogen, lower alkyloxy, hydroxy, -alkenylene-OH, or together with E2 forms a cyclic group including aryl, cyclic alkyl, heteroaryls, heterocyclic alkyl;
E2 is selected from the groups consisting of H, lower alkyl, halogen, SCN, lower alkyloxycarbonyl, lower alkyloxy, or together with L2 forms a cyclic group including aryl, cyclic alkyl, heteroaryl, or heterocyclic alkyl;
J2 is selected from the groups consisting of H, halogen, and lower alkyl;
Gxe2x80x3 is xe2x80x94Sxe2x80x94;
X2 is xe2x80x94OCH2xe2x80x94;
and pharmaceutically acceptable salts and prodrugs thereof. More preferred are such compounds wherein
R18 is selected from the group consisting of xe2x80x94H, methyl, and ethyl;
R12 and R13 are independently selected from the group consisting of xe2x80x94H, methyl, i-propyl, i-butyl, and benzyl, or together are connected via 2-5 carbon atoms to form a cycloalkyl group;
R14 is xe2x80x94OR17;
R17 is selected from the group consisting of methyl, ethyl, propyl, t-butyl, and benzyl; and
R15 and R16 are independently selected from the group consisting of lower alkyl, and lower aralkyl, or together R15 and R16 are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, and N.
Also more preferred are such compounds where A2 is NH2, L2 is selected from the group consisting of xe2x80x94Et and xe2x80x94Cl, E2 is selected from the group consisting of xe2x80x94SCN, xe2x80x94Et, and xe2x80x94Br, and J2 is xe2x80x94H. Particularly preferred are such compounds wherein 
is selected from the group consisting of 
wherein C* has S stereochemistry.
Preferred R18 groups include xe2x80x94H, methyl, and ethyl. More preferred is xe2x80x94H and methyl. Especially preferred is xe2x80x94H.
Preferred compounds include those wherein each R12 and R13 is independently selected from the group consisting of xe2x80x94H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, xe2x80x94CH2CH2xe2x80x94SCH3, phenyl, and benzyl, or together R12 and R13 are connected via 2-5 carbon atoms to form a cycloalkyl group. More preferred is each R12 and R13 is independently selected from the group consisting of xe2x80x94H, methyl, i-propyl, i-butyl, and benzyl, or together R12 and R13 are connected via 2-5 carbon atoms to form a cycloalkyl group. Also more preferred are such compounds wherein each R12 and R13 is independently selected from the group consisting of xe2x80x94H, methyl, i-propyl, and benzyl, or together R12 and R13 are connected via 4 carbon atoms to form a cyclopentyl group. Especially preferred are those compounds wherein R12 and R13 are both xe2x80x94H, both methyl, or R12 is H and R13 is selected from the group consisting of methyl, i-propyl, and benzyl. Most preferred are such compounds wherein is 1, and R12 is xe2x80x94H, then the carbon attached to R12 and R13 has S stereochemistry.
Preferably, n is an integer of from 1-2. More preferred is when n is 1.
Preferred compounds include those wherein each R14 is independently selected from the group consisting of xe2x80x94OR17, and xe2x80x94SR17; and R17 is selected from the group consisting of optionally substituted methyl, ethyl, propyl, t-butyl, and benzyl. More preferred are such compounds wherein each R14 is independently selected from the group consisting of xe2x80x94OR17; and R17 is selected from the group consisting of methyl, ethyl, propyl, and benzyl. Most preferred are such compounds wherein R17 is selected from the group consisting of ethyl, and benzyl.
Preferred are compounds wherein R15 is not H. More preferred are compounds wherein R15 and R16 are independently selected from the group consisting of lower alkyl, and lower aralkyl, or together R15 and R16 are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S. Also more preferred are compounds wherein R15 and R16 are independently selected from the group consisting of C1-C6 alkyl, or together R15 and R16 are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, N, and S. In one aspect, particularly preferred are compounds wherein xe2x80x94NR15R16 is a cyclic amine. Especially preferred are such compounds wherein xe2x80x94NR15R16 is selected from the group consisting of morpholinyl and pyrrolidinyl.
Preferred are compounds R16 is xe2x80x94(CR12R13)nxe2x80x94C(O)xe2x80x94R14;
More preferred are compounds where n is 1, and wherein
R18 is selected from the group consisting of xe2x80x94H, methyl, and ethyl;
R12 and R13 are independently selected from the group consisting of xe2x80x94H, methyl, i-propyl, i-butyl, and benzyl, or together are connected via 2-5 carbon atoms to form a cycloalkyl group;
R14 is xe2x80x94OR17;
R17 is selected from the group consisting of methyl, ethyl, propyl, t-butyl, and benzyl; and
R15 and R16 are independently selected from the group consisting of lower alkyl, and lower aralkyl, or together R15 and R16 are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, and N. Particularly preferred are such compounds that are of the formula: 
More preferred are such compounds wherein n is 1. Especially preferred are such compounds wherein when R12 and R13 are not the same, then H2Nxe2x80x94CR12R13xe2x80x94C(O)xe2x80x94R14 is an ester, or thioester of a naturally occurring amino acid; and R14 selected from the group consisting of xe2x80x94OR17 and xe2x80x94SR17.
In one aspect, preferred are compounds of formula IA or formula I wherein M is 
wherein:
A, E, and L are selected from the group consisting of xe2x80x94NR82, xe2x80x94NO2, xe2x80x94H, xe2x80x94OR7, xe2x80x94SR7, xe2x80x94C(O)NR42, halo, xe2x80x94COR11, xe2x80x94SO2R3, guandine, amidine, xe2x80x94NHSO2R5, xe2x80x94SO2NR42, xe2x80x94CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or together A and L form a cyclic group, or together L and E form a cyclic group, or together E and J form a cyclic group including aryl, cyclic alkyl, and heterocyclic;
J is selected from the group consisting of xe2x80x94NR82, xe2x80x94NO2, xe2x80x94H, xe2x80x94OR7, xe2x80x94SR7, xe2x80x94C(O)NR42, halo, xe2x80x94C(O)R11, xe2x80x94CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl, and aralkyl, or together with Y forms a cyclic group including aryl, cyclic alkyl and heterocyclic alkyl;
X3 is selected from the group consisting of -alkyl(hydroxy)-, -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all optionally substituted; with the proviso that X3 is not substituted with xe2x80x94COOR2, xe2x80x94SO3H, or xe2x80x94PO3R22;
Y3 is selected from the group consisting of xe2x80x94H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, xe2x80x94C(O)R3, xe2x80x94S(O)2R3, xe2x80x94C(O)xe2x80x94R11, xe2x80x94CONHR3, xe2x80x94NR22, and xe2x80x94OR3, all except H are optionally substituted;
R2 is selected from the group consisting of R3 and xe2x80x94H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
each R4 is independently selected from the group consisting of xe2x80x94H, and alkyl, or Together R4 and R4 form a cyclic alkyl group;
R5 is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic;
R7 is independently selected from the group consisting of xe2x80x94H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and xe2x80x94C(O)R10;
R8 is independently selected from the group consisting of xe2x80x94H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, xe2x80x94C(O)R10, or together they form a bidendate alkyl;
each R9 is independently selected from the group consisting of xe2x80x94H, alkyl, aralkyl, and alicyclic, or together R9 and R9 form a cyclic alkyl group;
R10 is selected from the group consisting of xe2x80x94H, lower alkyl, xe2x80x94NH2, lower aryl, and lower perhaloalkyl;
R11 is selected from the group consisting of alkyl, aryl, xe2x80x94NR22, and xe2x80x94OR2; and pharmaceutically acceptable prodrugs and salts thereof; with the provisos that:
a) when X3 is alkyl or alkene, then A is xe2x80x94N(R82);
b) X3 is not alkylamine and alkylaminoalkyl substituted with phosphonic esters and acids; and
c) A, L, E, J, and Y3 together may only form 0-2 cyclic groups.
More preferred are such compounds wherein X3 is not -alkoxyalkyl-, -alkyloxy-, -alkythioalkyl-, and -alkylthio-. Particularly preferred are such compounds with the additional proviso that when X3 is aryl or alkylaryl, said aryl or alkylaryl group is not linked 1,4 through a six-membered aromatic ring.
Especially preferred benzimidazole compounds include those wherein A, L, and E are independently selected from the group consisting of xe2x80x94H, xe2x80x94NR82, xe2x80x94NO2, hydroxy, halogen, xe2x80x94OR7, alkylaminocarbonyl, xe2x80x94SR7, lower perhaloalkyl, and C1-C5 alkyl, or together E and J together form a cyclic group; and wherein J is selected from the group consisting of xe2x80x94H, halogen, lower alkyl, lower hydroxyalkyl, xe2x80x94NR82, lower R82N-alkyl, lower haloalkyl, lower perhaloalkyl, lower alkenyl, lower alkynyl, lower aryl, heterocyclic, and alicyclic; and wherein Y is selected from the group consisting of alicyclic and lower alkyl; wherein X3 is selected from the group consisting of -heteroaryl-, -alkylcarbonylamino-, -alkylaminocarbonyl-, and -alkoxycarbonyl-. More preferred are such compounds wherein
R18 is selected from the group consisting of xe2x80x94H, methyl, and ethyl;
R12 and R13 are independently selected from the group consisting of xe2x80x94H, methyl, i-propyl, i-butyl, and benzyl, or together are connected via 2-5 carbon atoms to form a cycloalkyl group;
R14 is xe2x80x94OR17;
R17 is selected from the group consisting of methyl, ethyl, propyl, t-butyl, and benzyl; and
R15 and R16 are independently selected from the group consisting of lower alkyl, and lower aralkyl, or together R15 and R16 are connected via 2-6 atoms, optionally including 1 heteroatom selected from the group consisting of O, and N. Most preferred are such compounds wherein A is selected from the group consisting of xe2x80x94H, xe2x80x94NH2, xe2x80x94F, and xe2x80x94CH3;
L is selectedxe2x80x2from the group consisting of xe2x80x94H, xe2x80x94F, xe2x80x94OCH3, Cl and xe2x80x94CH3;
E is selected from the group consisting of xe2x80x94H, and xe2x80x94Cl;
J is selected from the group consisting of xe2x80x94H, halo, C1-C5 hydroxyalkyl, C1-C5 haloalkyl, C1-C5 R82N-alkyl, C1-C5 alicyclic, and C1-C5 alkyl;
X3 is selected from the group consisting of xe2x80x94CH2OCH2xe2x80x94, -methyleneoxycarbonyl-, and -furan-2,5-diyl-; and
Y is lower alkyl.
Also more preferred are such benzimidazoles where A is xe2x80x94NH2, L is xe2x80x94F, E is xe2x80x94H, J is ethyl, Y is isobutyl, and X3 is -furan-2,5-diyl-; or
where A is xe2x80x94NH2, L is xe2x80x94F, E is xe2x80x94H, J is N,N-dimethylaminopropyl, Y is isobutyl, and X3 is -furan-2,5-diyl-.
Particularly preferred are those compounds wherein 
is selected from the group consisting of 
wherein C* has S stereochemistry.
Preferably, oral bioavailability is at least 5%. More preferably, oral bioavailability is at least 10%.
The prodrugs of formula IA may have two isomeric forms around the phosphorus. Preferred is when the phosphorus is not chiral. Also preferred is when there is no chiral center in the amino groups attached to the phosphorus. Also preferred is when n is 1 and R12 is xe2x80x94H, then the carbon attached to R12 and R13 has,S stereochemistry.
In one aspect, preferred are compounds of formula X wherein A2 is selected from the group consisting of xe2x80x94H, xe2x80x94NH2, xe2x80x94CH3, xe2x80x94Cl, and xe2x80x94Br;
L2 is, xe2x80x94H, lower alkyl, halogen, lower alkyloxy, hydroxy, -alkenylene-OH, or together with E2 forms a cyclic group including aryl, cyclic alkyl, heteroaryls, heterocyclic alkyl;
E2 is selected from the groups consisting of H, lower alkyl, halogen, SCN, lower alkyloxycarbonyl, lower alkyloxy, or together with L2 forms a cyclic group including aryl, cyclic alkyl, heteroaryl, or heterocyclic alkyl;
J2 is selected from the groups consisting of H, halogen, and lower alkyl;
Gxe2x80x3 is xe2x80x94Sxe2x80x94;
X2 is xe2x80x94OCH2xe2x80x94; and
at least one Y group is xe2x80x94Oxe2x80x94; and pharmaceutically acceptable salts and prodrugs thereof. Also particularly preferred are such compounds where A2 is NH2, Gxe2x80x3 is xe2x80x94Sxe2x80x94, L2 is Et, E2 is SCN, and J2 is H. More preferred are such compounds wherein one Y is xe2x80x94Oxe2x80x94 and its corresponding R1 is optionally substituted phenyl, while the other Y is xe2x80x94NHxe2x80x94, and its corresponding R1 is xe2x80x94C(R2)2xe2x80x94COOR3. When R1 is xe2x80x94CHR3COOR3, then the corresponding xe2x80x94NR6xe2x80x94*CHR3COOR3, preferably has L stereochemistry.
Also more preferred are such compounds wherein one Y is xe2x80x94Oxe2x80x94, and its corresponding R1 is -phenyl, while the other Y is xe2x80x94NHxe2x80x94 and its corresponding R1 is xe2x80x94CH(Me)CO2Et.
In compounds of formula I, II, III, IV, V-1, V-2, VI, or X, preferably both Y groups are xe2x80x94Oxe2x80x94; or one Y is xe2x80x94Oxe2x80x94 and one Y is xe2x80x94NR6xe2x80x94. When only one Y is xe2x80x94NR6xe2x80x94, preferably the Y closest to W and Wxe2x80x2 is xe2x80x94Oxe2x80x94. Most preferred are prodrugs where both Y groups are xe2x80x94Oxe2x80x94;
In another particularly preferred aspect, both Y groups are xe2x80x94Oxe2x80x94, and R1 and R1 together are 
and V is phenyl substituted with 1-3 halogens. Especially preferred are such 3-bromo-4-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, and 3,5-dichlorophenyl.
In another particularly preferred aspect, one Y is xe2x80x94Oxe2x80x94 and its corresponding R1 is phenyl, or phenyl substituted with 1-2 substituents selected from xe2x80x94NHC(O)CH3, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94C(O)OCH2CH3, and xe2x80x94CH3; while the other Y is xe2x80x94NR6xe2x80x94 and its corresponding R1 is xe2x80x94C(R2)COOR3; each R2 is independently selected from xe2x80x94H, xe2x80x94CH3, and xe2x80x94CH2CH3. More preferred R6 is xe2x80x94H, and R1 attached to xe2x80x94NHxe2x80x94 is xe2x80x94CH(Me)CO2Et.
In general, preferred substituents, V, Z, W, and Wxe2x80x2 of formulae I, II, III, IV, V-1, V-2, VI or X are chosen such that they exhibit one or more of the following properties:
(1) enhance the oxidation reaction since this reaction is likely to be the rate determining step and therefore must compete with drug elimination processes.
(2) enhance stability in aqueous solution and in the presence of other non-p450 enzymes;
(3) enhance cell penetration, e.g. substituents are not charged or of high molecular weight since both properties can limit oral bioavailability as well as cell penetration;
(4) promote the (xcex2-elimination reaction following the initial oxidation by producing ring-opened products that have one or more of the following properties:
a) fail to recyclize;
b) undergo limited covalent hydration;
c) promote xcex2-elimination by assisting in the proton abstraction;
d) impede addition reactions that form stable adducts, e.g. thiols to the initial hydroxylated product or nucleophilic addition to the carbonyl generated after ring opening; and
e) limit metabolism of reaction intermediates (e.g. ring-opened ketone);
(5) lead to a non-toxic and non-mutagenic by-product with one or more of the following characteristics. Both properties can be minimized by using substituents that limit Michael additions, reactions, e.g.
a) electron donating Z groups that decrease double bond polarization;
b) W groups that sterically block nucleophilic addition to xcex2-carbon;
c) Z groups that eliminate the double bond after the elimination reaction either through retautomerization (enolxe2x86x92keto) or hydrolysis (e.g. enamine);
d) V groups that contain groups that add to the xcex1,xcex2-unsaturated ketone to form a ring;
e) Z groups that form a stable ring via Michael addition to double bond; and
f) groups that enhance detoxification of the by-product by one or more of the following characteristics:
(i) confine to liver; and
(ii) make susceptible to detoxification reactions (e.g. ketone reduction); and
(6) capable of generating a pharmacologically active product.
In another aspect, it is preferred when Y is xe2x80x94Oxe2x80x94, then R1 attached to xe2x80x94Oxe2x80x94 is independently selected from the group consisting of xe2x80x94H, optionally substituted aryl, optionally substituted alicyclic where the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, xe2x80x94C(R2)2OC(O)R3, xe2x80x94C(R2)2xe2x80x94Oxe2x80x94C(O)OR3, xe2x80x94C(R2)2OC(O)SR3, -alkyl-Sxe2x80x94C(O)R3, and -alkyl-Sxe2x80x94S-alkylhydroxy;
when Y is xe2x80x94NR6, then R1 attached to NR6 is independently selected from the group consisting of xe2x80x94H, xe2x80x94[C(R2)2]qxe2x80x94COOR3, xe2x80x94[C(R2)2]q xe2x80x94C (O)SR3; xe2x80x94C(R4)2COOR3, and -cycloalkylene-COOR3; or when either Y is independently selected from xe2x80x94Oxe2x80x94 and xe2x80x94NR6xe2x80x94, then together R1 and R1 are 
wherein
V, W, and Wxe2x80x2 are independently selected from the group consisting of xe2x80x94H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl, or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and Wxe2x80x2 are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
Z is selected from the group consisting of xe2x80x94CHR2OH, xe2x80x94CHR2OC(O)R3, xe2x80x94CHR2OC(S)R3, xe2x80x94CHR2OC(S)OR3, xe2x80x94CHR2OC(O)SR3, xe2x80x94CHR2OCO2R3, xe2x80x94OR2, xe2x80x94SR2, xe2x80x94R2, xe2x80x94NHCOR2, xe2x80x94NHCO2R3, xe2x80x94(CH2)pxe2x80x94OR2, and xe2x80x94(CH2)pxe2x80x94SR2;
p is an integer 2 or 3;
q is an integer 1 or 2;
with the provisos that:
a) V, Z, W, Wxe2x80x2 are not all xe2x80x94H;
b) when Z is xe2x80x94R2, then at least one of V, W, and Wxe2x80x2 is not xe2x80x94H, alkyl, aralkyl, or alicyclic; and
c) both Y groups are not xe2x80x94NR6xe2x80x94;
R2 is selected from the group consisting of R3 and xe2x80x94H;
R3 is selected from the group consisting of alkyl, aryl; alicyclic, and aralkyl;
R6 is selected from the group consisting of xe2x80x94H, and lower alkyl.
More preferred are such compounds wherein when both Y groups are xe2x80x94Oxe2x80x94, then R1 is independently selected from the group consisting of optionally substituted aryl, optionally substituted benzyl, xe2x80x94C(R2)2OC(O)R3, xe2x80x94C(R2)2OC(O)OR3, and xe2x80x94H; and
when Y is xe2x80x94NR6xe2x80x94, then the R1 attached to said xe2x80x94NR6xe2x80x94 group is selected from the group consisting of xe2x80x94C(R4)2xe2x80x94COOR3, and xe2x80x94C(R2)2COOR3; and the other Y group is xe2x80x94Oxe2x80x94 and then R1 attached to said xe2x80x94Oxe2x80x94 is selected from the group consisting of optionally substituted aryl, xe2x80x94C(R2)2OC(O)R3, and xe2x80x94C(R2)2OC(O)OR3.
In another aspect, when one Y is xe2x80x94Oxe2x80x94, then its corresponding R1 is phenyl, and the other Y is xe2x80x94NHxe2x80x94, and its corresponding R1 is xe2x80x94CH2CO2Et.
In another preferred aspect, when one Y is xe2x80x94Oxe2x80x94, its corresponding R1 is phenyl, and the other Y is xe2x80x94NHxe2x80x94 and its corresponding R1 is xe2x80x94C(Me)2CO2Et.
In another preferred aspect, when one Y is xe2x80x94Oxe2x80x94, its corresponding R1 is 4-NHC(O)CH3-phenyl, and the other Y is xe2x80x94NHxe2x80x94, and its corresponding R1 is xe2x80x94CH2COOEt.
In another preferred aspect, when one Y is xe2x80x94Oxe2x80x94, its corresponding R1 is 2-CO2Et-phenyl, and the other Y is xe2x80x94NHxe2x80x94 and its corresponding R1 is xe2x80x94CH2CO2Et.
In another preferred aspect, when one Y is xe2x80x94Oxe2x80x94, then its corresponding R1 is 2-CH3-phenyl, and the other Y is xe2x80x94NH, and its corresponding, R1 is xe2x80x94CH2CO2Et.
In another aspect, preferred are compounds wherein both Y groups are xe2x80x94Oxe2x80x94, and R1 is aryl, or xe2x80x94C(R2)2-aryl.
Also preferred are compounds wherein both Y groups are Oxe2x80x94, and at least one R1 is selected from the group consisting of xe2x80x94C(R2)2xe2x80x94OC(O)R3, and xe2x80x94C(R2)2xe2x80x94OC(O)OR3.
In another aspect, preferred are compounds wherein both Y groups are xe2x80x94Oxe2x80x94 and at least one R1 is -alkyl-Sxe2x80x94S-alkylhydroxyl, -alkyl-Sxe2x80x94C(O)R3, and -alkyl-Sxe2x80x94Sxe2x80x94S-alkylhydroxy, or together R1 and R1 are -alkyl-Sxe2x80x94S-alkyl- to form a cyclic group.
In one aspect, particularly preferred are compounds wherein both Y groups are xe2x80x94Oxe2x80x94, and R1 is H.
In another aspect, particularly preferred are compounds where both Y groups are xe2x80x94Oxe2x80x94, and R1 is xe2x80x94CH2OC(O)OEt.
More preferred are compounds wherein at least one Y is xe2x80x94Oxe2x80x94, and together R1 and R1 are 
wherein
V, W, and Wxe2x80x2 are independently selected from the group consisting of xe2x80x94H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl; substituted heteroaryl, 1-alkenyl, and 1-alkynyl, or
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and Wxe2x80x2 are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
Z is selected from the group consisting of xe2x80x94CHR2OH, xe2x80x94CHR2OC(O)R3, xe2x80x94CHR2OC(S)R3, xe2x80x94CHR2OC(S)OR3, xe2x80x94CHR2OC(O)SR3, xe2x80x94CHR2OCO2R3, xe2x80x94OR2, xe2x80x94SR2, xe2x80x94R2, xe2x80x94NHCOR2, NHCO2R3, xe2x80x94(CH2)pxe2x80x94OR2, and xe2x80x94(CH2)pxe2x80x94SR2;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, Wxe2x80x2 are not all xe2x80x94H;
b) when Z is xe2x80x94R2, then at least one of V, W, and Wxe2x80x2 is not xe2x80x94H, alkyl, aralkyl, or alicyclic; and
c) both Y groups are not xe2x80x94NR6xe2x80x94;
R2 is selected from the group consisting of R3 and xe2x80x94H;
R3 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R6 is selected from the group consisting of xe2x80x94H, and lower alkyl.
In an other aspect, more preferred are compounds wherein one Y is xe2x80x94Oxe2x80x94, and R1 is optionally substituted aryl; and the other Y is xe2x80x94NR where R1 on said xe2x80x94NR6xe2x80x94 is selected from the group consisting of xe2x80x94C(R4)2COOR3, and xe2x80x94C(R2)2C(O)OR3. Particularly preferred are such compounds where R1 attached to xe2x80x94Oxe2x80x94 is -phenyl, and R1 to xe2x80x94NHxe2x80x94 is xe2x80x94CH(Me)CO2Et, and xe2x80x94NH*CH(Me)CO2Et is in the L configuration.
Especially preferred are such compounds where R1 attached to xe2x80x94Oxe2x80x94 is selected from the group consisting of phenyl and phenyl substituted with 1-2 substituents selected from the group consisting of xe2x80x94NHAc, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94COOEt, and xe2x80x94CH3; and R1 attached to NR6 is xe2x80x94C(R2)2COOR3 where R2 and R3 independently is xe2x80x94H, xe2x80x94CH3, and xe2x80x94Et. Of such compounds, when R1 attached to xe2x80x94Oxe2x80x94 is phenyl substituted with xe2x80x94NHAc or xe2x80x94COOEt, then preferably any xe2x80x94NHAc is at the 4-position, and any xe2x80x94COOEt is at the 2-position. More preferred are such compounds where the substituents on the substituted phenyl is 4-NHC(O)CH3, xe2x80x94Cl, xe2x80x94Br, 2-C(O)OCH3CH3, or xe2x80x94CH3.
More preferred V groups of formula 6-i are aryl, substituted aryl, heteroaryl, and substituted heteoaryl. Preferably Y is. xe2x80x94Oxe2x80x94. Particularly preferred aryl and substituted aryl groups include phenyl, and phenyl substituted with 1-3 halogens. Especially preferred are 3,5-dichlorophenyl, 3-bromo-4-fluorophenyl, 3-chlorophenyl, and 3-bromophenyl.
It is also especially preferred when V is selected from the group consisting of monocyclic heteroaryl and monocyclic substituted heteroaryl containing at least one nitrogen atom. Most preferred is when such heteroaryl and substituted heteroaryl is 4-pyridyl, and 3-bromopyridyl, respectively.
It is also preferred when together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma positions to the Y attached to phosphorus. In such compounds preferably said aryl group is an optionally substituted monocyclic aryl group and the connection between Z and the gamma position of the aryl group is selected from the group consisting of O, CH2, CH2CH2, OCH2 or CH2O.
In another aspect, it is preferred when together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and monosubstituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkosycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorus. In such compounds, it is more preferred when together V and W form a cyclic group selected from the group consisting of xe2x80x94CH2xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94, CH2CH(OCOR3)xe2x80x94CH2xe2x80x94, and xe2x80x94CH2CH(OC02)R3)xe2x80x94CH2xe2x80x94.
Another preferred V group is 1-alkene. Oxidation by p450 enzymes is known to occur at benzylic and allylic carbons.
In one aspect, a preferred V group is xe2x80x94H, when Z is selected from the group consisting of xe2x80x94CHR2OH, xe2x80x94CHR2OCOR3, and xe2x80x94CHR2OCO2R3.
In another aspect, when V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, preferred Z groups include-OR2, xe2x80x94SR2, xe2x80x94CHR2N3, xe2x80x94R2, xe2x80x94NR22, xe2x80x94OCOR2, xe2x80x94OCO2R3, xe2x80x94SCOR3, xe2x80x94SCO2R3, xe2x80x94NHCOR2, xe2x80x94NHCO2R3, xe2x80x94CH2NHaryl, xe2x80x94(CH2)pOR2, and xe2x80x94(CH2)pxe2x80x94SR2. More preferred Z groups include-OR2, xe2x80x94R2, xe2x80x94OCOR2, xe2x80x94OCO2R3, xe2x80x94CH3, xe2x80x94NHCOR2, xe2x80x94NHCO2R3, xe2x80x94(CH2pxe2x80x94OR2, and, xe2x80x94(CH2)pxe2x80x94SR2. Most preferred Z groups include xe2x80x94OR2, xe2x80x94H , xe2x80x94OCOR2, xe2x80x94OCO2R3, and xe2x80x94NHCOR2.
Preferred W and Wxe2x80x2 groups include H, R3, aryl, substituted aryl, heteroaryl, and substituted aryl. Preferably, W and Wxe2x80x2 are the same group. More preferred is when W and Wxe2x80x2 are H.
In one aspect, prodrugs of formula 6-i are preferred: 
wherein
V is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl, 1-alkenyl, and 1-alkynyl. More preferred V groups of formula VI are aryl, substituted, heteroaryl, and substituted heteoaryl. Preferably Y is xe2x80x94Oxe2x80x94. Particularly preferred aryl and substituted aryl groups include phenyl and substituted phenyl. Particularly preferred heteroaryl groups include monocyclic substiutted and unsubstituted heteroaryl groups. Especially preferred are 4-pyridyl and 3-bromopyridyl.
In one aspect, the compounds of formula VI preferably have a group Z which is H, alkyl, alicyclic, hydroxy, alkoxy, 
or NHCOR. Preferred are such groups in which Z decreases the propensity of the byproduct, vinyl aryl ketone to undergo Michael additions. Preferred Z groups are groups that donate electrons to the vinyl group which is a known strategy for decreasing the propensity of xcex1,xcex2-unsaturated carbonyl compounds to undergo a Michael addition. For example, a methyl group in a similar position on acrylamide results in no mutagenic activity whereas the unsubstituted vinyl analog is highly mutagenic. Other groups could serve a similar function, e.g. Zxe2x95x90OR, NHAc, etc. Other groups may also prevent the Michael addition especially groups that result in removal of the double bond altogether such as Zxe2x95x90OH, xe2x80x94OC(O)R, xe2x80x94OCO2R, and NH2, which will rapidly undergo retautomerization after the elimination reaction. Certain W and Wxe2x80x2 groups are also advantageous in this role since the group(s) impede the addition reaction to the xcex2-carbon or destabilize the product. Another preferred Z group is one that contains a nucleophilic group capable of adding to the xcex1,xcex2-unsaturated double bond after the elimination reaction i.e. (CH2)pSH or (CH2)nOH where p is 2 or 3. Yet another preferred group is a group attached to V which is capable of adding to the xcex1,xcex2-unsaturated double bond after the elimination reaction: 
In another aspect, prodrugs of formula 7-i are preferred: 
wherein
Z is selected from the group consisting of: xe2x80x94CHR2OH, xe2x80x94CHR2OCOR3, xe2x80x94CHR2OC(S)R3, xe2x80x94CHR2OCO2R3, xe2x80x94CHR2OC(O)SR3, and xe2x80x94CHR2OC(S)OR3. Preferably Y is xe2x80x94Oxe2x80x94. More preferred groups include xe2x80x94CHR2OH, xe2x80x94CHR2OC(O)R3, and xe2x80x94CHR2OCO2R3.
In another aspect, prodrugs of formula 8-i are preferred: 
wherein
Zxe2x80x2 is selected from the group consisting of xe2x80x94OH, xe2x80x94OC(O)R3, xe2x80x94OCO2 R3, and xe2x80x94OC(O)S R3;
D4 and D3 are independently selected from the group consisting of xe2x80x94H, alkyl, OR2, xe2x80x94OH, and xe2x80x94OC(O)R3; with the proviso that at least one of D4 and D3 are xe2x80x94H. Preferably Y is xe2x80x94Oxe2x80x94.
In one preferred embodiment, Wxe2x80x2 and Z are xe2x80x94H, W and V are both the same aryl, substituted aryl, heteroaryl, or substituted heteroaryl such that the phosphonate prodrug moiety: 
has a plane of symmetry. Preferably Y is xe2x80x94Oxe2x80x94.
In another preferred embodiment, W and Wxe2x80x2 are H, V is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, and Z is selected from the group consisting of xe2x80x94H, OR2, and xe2x80x94NHCOR2. More preferred are such compounds where Z is xe2x80x94H.
p450 oxidation can be sensitive to stereochemistry which might either be at phosphorus or at the carbon bearing the aromatic group. The prodrugs of the present invention have two isomeric forms around the phosphorus. Preferred is the stereochemistry that enables both oxidation and the elimination reaction. Preferred is the cis-stereochemistry.
The preferred compounds of formula 8-i utilize a Zxe2x80x2 group that is capable of undergoing an oxidative reaction that yields an unstable intermediate which via elimination reactions breaks down to the corresponding R5xe2x80x94Xxe2x80x94PO32xe2x88x92, R5xe2x80x94Xxe2x80x94P(O)(NHR6)2, or R5xe2x80x94Xxe2x80x94P(O)(Oxe2x88x92)NHR6). Especially preferred Zxe2x80x2 groups is OH. Groups D4 and D3 are preferably hydrogen, alkyl, and xe2x80x94OR2, xe2x80x94OC(O)R3, but at least one of D4 or D3 must be H.
The following prodrugs of formulae I, II, III, IV, V-1, V-2, VI, and X are preferred:
Acyloxyalkyl esters;
Alkoxycarbonyloxyalkyl esters;
Aryl esters;
Benzyl and substituted benzyl esters;
Disulfide containing esters;
Substituted (1,3-dioxolen-2-one)methyl esters;
Substituted 3-phthalidyl esters;
Cyclic-[5-hydroxycyclohexan-1,3-diyl) diesters and hydroxy protected forms;
Cyclic-[2-hydroxymethylpropan-1,3-diyl] diesters and hydroxy protected forms;
Cyclic-(1-arylpropan-1,3-diyl);
Bis Omega substituted lactone esters; and all mixed esters resulted from possible combinations of above esters;
More preferred are the following:
Bis-pivaloyloxymethyl esters;
Bis-isobutyryloxymethyl esters;
Cyclic-[2-hydroxymethylpropan-1,3-diyl] diester;
Cyclic-[2-acetoxymethylpropan-1,3-diyl] diester;
Cyclic-[2-methyloxycarbonyloxymethylpropan-1,3-diyl] diester;
Cyclic-[1-phenylpropan-1,3-diyl] diesters;
Cyclic-[1-(2-pyridyl)propan-1,3-diyl)] diesters;
Cyclic-[1-(3-pyridyl)propan-1,3-diyl] diesters;
Cyclic-[1-(4-pyridyl)propan-1,3-diyl] diesters;
Cyclic-[5-hydroxycyclohexan-1,3-diyl] diesters and hydroxy protected forms;
Bis-benzoylthiomethyl esters;
Bis-benzoylthioethyl esters;
Bis-benzoyloxyethyl esters;
Bis-p-fluorobenzoyloxymethyl esters;
Bis-6-chloronicotinoyloxymethyl esters;
Bis-5-bromonicotinoyloxymethyl esters;
Bis-thiophenecarbonyloxymethyl esters;
Bis-2-furoyloxymethyl esters;
Bis-3-furoyloxymethyl esters;
Diphenyl esters;
Bis-(4-methoxyphenyl) esters
Bis-(2-methoxyphenyl) esters;
Bis-(2-ethoxyphenyl) esters;
Mono-(2-ethoxyphenyl) esters;
Bis-(4-acetamidophenyl) esters;
Bis-(4-acetoxyphenyl) esters;
Bis-(4-hydroxyphenyl) esters;
Bis-(2-acetoxyphenyl) esters;
Bis-(3-acetoxyphenyl) esters;
Bis-(4-morpholinophenyl) esters;
Bis[4-(1-triazolophenyl) esters;
Bis-(3-N,N-dimethylaminophenyl) esters;
Bis-(1,2,3,4-tetrahydronapthalen-2-yl) esters;
Bis-(3-chloro-4-methoxy)benzyl esters;
Bis-(3-bromo-4-methoxy)benzyl esters;
Bis-(3-cyano-4-methoxy)benzyl esters;
Bis-(3-chloro-4-acetoxy)benzyl esters;
Bis-(3-bromo-4-acetoxy)benzyl esters;
Bis-(3-cyano-4-acetoxy)benzyl esters;
Bis-(4-chloro)benzyl esters;
Bis-(4-acetoxy)benzyl esters;
Bis-(3,5-dimethoxy-4-acetoxy)benzyl esters;
Bis-(3-methyl-4-acetoxy)benzyl esters;
Bis-(benzyl)esters;
Bis-(3-methoxy-4-acetoxy)benzyl esters;
Bis-(6xe2x80x2-hydroxy-3xe2x80x2,4xe2x80x2-dithia)hexyl esters;
Bis-(6xe2x80x2-acetoxy-3xe2x80x2,4xe2x80x2-dithia)hexyl esters;
(3,4-dithiahexan-1,6-diyl) esters;
Bis-(5-methyl-1,3-dioxolen-2-one-4-yl)methyl esters;
Bis-(5-ethyl-1,3-dioxolen-2-one-4-yl)methyl esters;
Bis-(5-tert-butyl-1,3-dioxolen-2-one-4-yl)methyl esters;
Bis-3-(5,6,7-trimethoxy)phthalidyl esters;
Bis-(cyclohekyloxycarbonyloxymethyl) esters;
Bis-(isopropyloxycarbonyloxymethyl) esters;
Bis-(ethyloxycarbonyloxymethyl) esters;
Bis-(methyloxycarbonyloxymethyl) esters;
Bis-(isopropylthiocarbonyloxymethyl) esters;
Bis-(phenyloxycarbonyloxymethyl) esters;
Bis-(benzyloxycarbonyloxymethyl) esters;
Bis-(phenylthiocarbonyloxymethyl) esters;
Bis-(p-methoxyphenoxycarbonyloxymethyl) esters;
Bis-(m-methoxyphenoxycarbonyloxymethyl) esters;
Bis-(o-methoxyphenoxycarbonyloxymethyl) esters;
Bis-(o-methylphenoxycarbonyloxymethyl) esters;
Bis-(p-chlorophenoxycarbonyloxymethyl) esters;
Bis-(1,4-biphenoxycarbonyloxymethyl) esters;
Bis-[(2-phthalimidoethyl)oxycarbonyloxymethyl]esters;
Bis-(N-phenyl-N-methylcarbamoyloxymethyl) esters;
Bis-(2,2,2-trichloroethyl) esters;
Bis-(2-bromoethyl) esters;
Bis-(2-iodoethyl) esters;
Bis-(2-azidoethyl) esters;
Bis-(2-acetoxyethyl) esters;
Bis-(2-aminoethyl) esters;
Bis-(2-N,N-dimethylaminoethyl) esters;
Bis-(2-aminoethyl) esters;
Bis-(methoxycarbonylmethyl) esters;
Bis-(2-aminoethyl) esters;
Bis-[N,N-di(2-hydroxyethyl)]carbamoylmethylesters;
Bis-(2-aminoethyl) esters;
Bis-(2-methyl-5-thiazolomethyl) esters;
Bis-(bis-2-hydroxyethylcarbamoylmethyl) esters.
O-phenyl-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh)(N(H)xe2x80x94CH(Me)CO2Et)
O-phenyl-[N-(1-methoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh)(N(H)xe2x80x94CH(Me)CO2Me)
O-(3-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-3-Cl)(NH-CH(Me)CO2Et)
O-(2-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-2-Cl)(NHxe2x80x94CH(Me)CO2Et)
O-(4-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-4-Cl)(NHxe2x80x94CH(Me)CO2Et)
O-(4-acetamidophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-4-NHAc)(NHxe2x80x94CH(Me)CO2Et)
O-(2-ethoxycarbonylphenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-2-CO2Et)(NHxe2x80x94CH(Me)CO2Et)
O-phenyl-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh)(NHxe2x80x94C(Me)2CO2Et)
O-phenyl-[N-(1-methoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh)(NHxe2x80x94C(Me)2CO2Me)
O-(3-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-3-Cl)(NH-C(Me)2CO2Et)
O-(2-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-2-Cl)(NH-C(Me)2CO2Et)
O-(4-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-4-Cl)(NHxe2x80x94C(Me)2CO2Et).
O-(4-acetamidophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-4-NHAc)(NHxe2x80x94C(Me)2CO2Et)
O-(2-ethoxycarbonylphenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates (-P(O)(OPh-2-CO2Et)(NHxe2x80x94C(Me)2CO2Et)
O-phenyl-[N-(ethoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh)(NHxe2x80x94CH2CO2Et)
O-phenyl-[N-(methoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh)(NHxe2x80x94CH2CO2Me)
O-(3-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh-3-Cl)(NHxe2x80x94CH2CO2Et)
O-(2-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh-2-Cl)(NHxe2x80x94CH2CO2Et)
O-(4-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh-4-Cl)(NHxe2x80x94CH2CO2Et)
O-(4-acetamidophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh-4-NHAc)(NHxe2x80x94CH2C2Et)
O-(2-ethoxycarbonylphenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(Q)(OPh-2-CO2Et)(NHxe2x80x94CH2CO2Et)
Most preferred are the following:
Bis-pivaloyloxymethyl esters;
Bis-isobutyryloxymethyl esters;
Cyclic-(2-hydroxymethylpropan-1,3-diyl) ester;
Cyclic-(2-acetoxymethylpropan-1,3-diyl) ester;
Cyclic-(2-methyloxycarbonyloxymethylpropan-1,3-diyl) ester;
Cyclic-(2-cyclohexylcarbonyloxymethylpropan-1,3-diyl) ester;
Cyclic-[phenylpropan-1,3-diyl] diesters;
Cyclic-[1-(2-pyridyl)propan-1,3-diyl)] diesters;
Cyclic-[1-(3-pyridyl)propan-1,3-diyl] diesters;
Cyclic-[1-(4-pyridyl)propan-1,3-diyl] diesters;
Cyclic-[5-hydroxycyclohexan-1,3-diyl] diesters and hydroxy protected forms;
Bis-benzoylthiomethyl esters;
Bis-benzoylthioethylesters;
Bis-benzoyloxymethyl esters;
Bis-p-fluorobenzoyloxymethyl esters;
Bis-6-chloronicotinoyloxymethyl esters;
Bis-5-bromonicotinoyloxymethyl esters;
Bis-thiophenecarbonyloxymethyl esters;
Bis-2-furoyloxymethyl esters;
Bis-3-furoyloxymethyl esters;
Diphenyl esters;
Bis-(2-methylphenyl) esters;
Bis-(2-methoxyphenyl) esters;
Bis-(2-ethoxyphenyl) esters;
Bis-(4-methoxyphenyl) esters;
Bis-(3-bromo-4-methoxy benzyl) esters;
Bis-(4-acetoxybenzyl) esters;
Bis-(3,5-dimethoxy-4-acetoxybenzyl) esters;
Bis-(3-methyl-4-acetoxybenzyl) esters;
Bis-(3-methoxy-4-acetoxybenzyl) esters;
Bis-(3-chloro-4-acetoxybenzyl) esters;
Bis-(cyclohekyloxycarbonyloxymethyl) esters;
Bis-(isopropyloxycarbonyloxymethyl) esters;
Bis-(ethyloxycarbonyloxymethyl) esters,
Bis-(methyloxycarbonyloxymethyl) esters;
Bis-(isopropylthiocarbonyloxymethyl) esters;
Bis-(phenyloxycarbonyloxymethyl) esters;
Bis-(benzyloxycarbonyloxymethyl) esters;
Bis-(phenylthiocarbonyloxymethyl) esters;
Bis-(p-methoxyphenoxycarbonyloxymethyl) esters;
Bis-(m-methoxyphenoxycarbonyloxymethyl) esters;
Bis-(o-methoxyphenoxycarbonyloxymethyl) esters;
Bis-(o-methylphenoxycarbonyloxymethyl) esters;
Bis-(p-chlorophenoxycarbonyloxymethyl) esters;
Bis-(1,4-biphenoxycarbonyloxymethyl) esters;
Bis-[(2-phthalimidoethyl)oxycarbonyloxymethyl]esters;
Bis-(6-hydroxy-3,4-dithia)hexyl esters;
Cyclic-(3,4-dithiahexan-1,6-diyl) esters;
Bis-(2-bromoethyl) esters;
Bis-(2-aminoethyl) esters;
Bis-(2-N,N-diaminoethyl) esters;
O-phenyl-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh)(NHxe2x80x94*CH(Me)CO2Et)
O-phenyl-[N-(1-methoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh)(NHxe2x80x94*CH(Me)CO2Me)
O-(3-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-3-Cl)(NHxe2x80x94*CH(Me)CO2Et)
O-(2-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-2-Cl)(NHxe2x80x94*CH(Me)CO2Et)
O-(4-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-4-Cl)(NHxe2x80x94*CH(Me)CO2Et)
O-(4-acetamidophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-4-NHAc)(NHxe2x80x94*CH(Me)CO2Et)
O-(2-ethoxycarbonylphenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-2-CO2Et)(NHxe2x80x94*CH(Me)CO2Et)
O-phenyl-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh)(NHxe2x80x94C(Me)2CO2Et)
O-phenyl-[N-(1-methoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh)(NHxe2x80x94C(Me)2CO2Me)
O-(3-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-3-Cl)(NHxe2x80x94C(Me)2CO2Et)
O-(2-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-2-Cl)(NHxe2x80x94C(Me)2CO2Et)
O-(4-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-4-Cl)(NHxe2x80x94O(Me)2CO2Et)
O-(4-acetamidophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-4-NHAc)(NHxe2x80x94C(Me)2CO2Et)
O-(2-ethoxycarbonylphenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates (xe2x80x94P(O)(OPh-2-CO2Et)(NHxe2x80x94C(Me)2CO2Et)
In the above prodrugs an asterisk (*) on a carbon refers to the L-configuration.
O-phenyl-[N-(ethoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh)(NHxe2x80x94CH2CO2Et)
O-phenyl-[N-(methoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh)(NHxe2x80x94CH2CO2Me)
O-(3-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh-3-Cl)(NHxe2x80x94CH2CO2Et)
O-(2-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh-2-Cl)(NHxe2x80x94CH2C02Et)
O-(4-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh-4-Cl)(NHxe2x80x94CH2CO2Et)
O-(4-acetamidophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates (xe2x80x94P(O)(OPh-4-NHAc)(NHxe2x80x94CH2CO2Et)
O-(2-ethoxycarbonylphenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates(xe2x80x94P(O)(OPh-2-CO2Et)(NHxe2x80x94CH2CO2Et)
The compounds designated in Table 1 refer to preferred compounds of formula I-A where M is R5xe2x80x94Xxe2x80x94 as defined in the following formulae: formula i, formula ii, and formula iii. 
In the above formulae i, ii, and iii, R5 may be substituted by A and B. The preferred compounds of formulae i, ii, and iii are listed in Table 1 by designated numbers assigned to R5, A, B, Q1, and Q2 in the above formulae i, ii, and iii according to the following convention: Q1.Q2. R5.B.A. For each moiety, structures assigned to a number shown in the following tables for R5, A, B, Q1 and Q2.
Variable R5 is divided into two groups, each listing four different structures.
Compounds named in Table 1 of formulae i, ii, and iii wherein the R5 moieties are assigned the following numbers:
Variables Q1 and Q2 are divided into three groups, each listing eight different substituents.
Q1 and Q2 moieties are assigned the following numbers:
Group 1:
Q1 and Q2 
1. xe2x80x94NHxe2x80x94CH2-C(O)R14
2. xe2x80x94NHxe2x80x94CH(CH3)xe2x80x94C(O)R14
3. xe2x80x94NHxe2x80x94C(CH3)2-C(O)R14
4. xe2x80x94NHxe2x80x94C(CH3)2CH2-C(O)R14
5. xe2x80x94NHxe2x80x94CH(CH(CH3)2))xe2x80x94C(O)R14
6. xe2x80x94NHxe2x80x94CH(CH2(CH(CH3)2)))xe2x80x94C(O)R14
7. xe2x80x94NHxe2x80x94CH(CH2CH2SCH3)xe2x80x94C(O)R14
8. xe2x80x94NHxe2x80x94CH(CH2SCH2Ph)xe2x80x94C(O)R14
Group 2:
Q1 and Q2 
1. xe2x80x94NHxe2x80x94CH2CH2-C(O)R14
2. xe2x80x94NHxe2x80x94CH(CH2CH2COR14)xe2x80x94C(O)R14
3. xe2x80x94NHxe2x80x94CH(CH2COR14)xe2x80x94C(O)R14
4. xe2x80x94NHxe2x80x94CH(CH2CONH2)xe2x80x94C(O)R14
5. xe2x80x94NHxe2x80x94CH(COR14)CH2-C(O)R:4
6. xe2x80x94NHxe2x80x94CH(CH2OR17)xe2x80x94C(O)R14
7. xe2x80x94NHxe2x80x94CH(CH2CH2COR14)xe2x80x94C(O)R14
8. xe2x80x94NHxe2x80x94CH(CH2OH)xe2x80x94C(O)R14
Group 3:
Q1 and Q2 
1. xe2x80x94NHxe2x80x94CH(CH2-C6H5OH)xe2x80x94C(O)R14
2. xe2x80x94NHxe2x80x94C(c-propyl)xe2x80x94C(O)R14
3. xe2x80x94NHxe2x80x94C(c-pentyl)xe2x80x94C(O)R14
4. xe2x80x94NHxe2x80x94C(c-hexyl)xe2x80x94C(O)R14
5. xe2x80x94NHxe2x80x94CH(CH2Ph)xe2x80x94C(O)R14
6. xe2x80x94N(CH3)xe2x80x94CH2CO)xe2x80x94C(O)R14
8. xe2x80x94NR18R19
where R4 is selected from the groups consisting of OMe, OEt, OBn, O-tBu, O-nPr, OPh, xe2x80x94N(Me)2, Morpholine, SMe, SEt; R17 is methyl, ethyl, benzyl, and propyl; R18 is H, Me, Et, Bn, Pr and Ph and R19 is Me, Et, Bn, Pr and Ph; R18 and R19 is morpholinyl and pyrrolidinyl.
Thus, the compound 3.3.1.2.1 in Group 1 corresponds to the structure below for formula i: 
and when R4 is ethoxy the structure would be 
The numbers designated in Table 1 also refer to preferred benzothiazole and benzoxazole compounds of formula X. These preferred compounds are shown in formulae iv and v. 
The preferred compounds of formulae iv and formula v are listed in Table 1 by designated numbers assigned to A, B, D, Q1, and Q2 in the above formulae iv and v, according to the following convention: Q1.Q2.A.B.D. For each moiety, structures assigned to a number shown in the following tables for A, B, D, Q1 and Q2.
Variables Q1 and Q2 are divided into three groups, each listing eight different substituents.
Group 1:
Q1 and Q2 moieties are assigned the following numbers:
Q1 and Q2 
1. xe2x80x94NHxe2x80x94CH2-C(O)R14
2. xe2x80x94NHxe2x80x94CH(CH3)xe2x80x94C(O)R14
3. xe2x80x94NHxe2x80x94C(CH3)2-C(O)R14
4. xe2x80x94NHxe2x80x94C(CH3)2CH2-C(O)R14
5. xe2x80x94NHxe2x80x94CH(CH(CH3)2))xe2x80x94C(O)R14
6. xe2x80x94NHxe2x80x94CH(CH2(CH(CH3)2)))xe2x80x94C(O)R14
7. xe2x80x94NHxe2x80x94CH(CH2CH2SCH3)xe2x80x94C(O)R14
8. xe2x80x94NHxe2x80x94CH(CH2SCH2Ph)xe2x80x94C(O)R14
Group 2:
Q1 and Q2 
1. xe2x80x94NHxe2x80x94CH2CH2-C(O)R14
2. xe2x80x94NHxe2x80x94CH(CH2CH2COR14)xe2x80x94C(O)R14
3. xe2x80x94NHxe2x80x94CH(CH2COR14)xe2x80x94C(O)R14
4. xe2x80x94NHxe2x80x94CH(CH2CONH2)xe2x80x94C(O)R14
5. xe2x80x94NHxe2x80x94CH(COR14)CH2-C(O)R14
6. xe2x80x94NHxe2x80x94CH(CH2OR17)xe2x80x94C(O)R14
7. xe2x80x94NHxe2x80x94CH(CH2CH2COR14)xe2x80x94C(O)R14
8. xe2x80x94NHxe2x80x94CH(CH2OH)xe2x80x94C(O)R14
Group 3:
Q1and Q2 
1. xe2x80x94NHxe2x80x94CH(CH2-C6H5OH)xe2x80x94C(O)R14
2. xe2x80x94NHxe2x80x94C(c-propyl)xe2x80x94C(O)R14
3. xe2x80x94NHxe2x80x94C(c-pentyl)xe2x80x94C(O)R14
4. xe2x80x94NHxe2x80x94C(c-hexyl)xe2x80x94C(O)R14
5. xe2x80x94NHxe2x80x94CH(CH2Ph)xe2x80x94C(O)R14
6. xe2x80x94N(CH3)xe2x80x94CH2-C(O)R14
8. xe2x80x94NR18R19
Variable B is divided into three groups, each listing eight different substituents.
Group 3 for Variable B can only be combined with Group 3 variable for D.
Variable D is divided into three groups, each listing four different substituents.
Compounds named in Table 1 of formulae iv and v wherein the A moieties are assigned the following numbers:
where R4 is selected from the groups consisting of OMe, OEt, OBn, O-tBu, O-nPr, OPh, xe2x80x94N(Me)2, morpholine, SMe, SEt; R17 is methyl, ethyl, benzyl, and propyl; R18 is H, Me, Et, Bn, Pr and Ph and R19 is Me, Et, Bn, Pr and Ph; R18 and R19 is morpholinyl and pyrrolidinyl
Thus, the compound 2.2.1.7.4 from Group 1 for B, D, Q1 and Q2 corresponds to the structure below for formula iv 
and when R4 is ethoxy the structure would be 
Similarly, in group 3 for variable B, the compound 2.2.1.7.4 corresponds to the structure below for formula iv 
and when R4 is ethoxy the structure would be 
The best mode of practicing the claimed invention is with compounds of Example numbers 48.6, 48.9, 48.15, and 48.20.
Preferred insulin sensitizers are compounds disclosed in the following publications and patents:
(1) Tamura et al. W09737688
(2) Nagao et al., Eur. Pat. Appl. EP-787727
(3) Kallam et al. Can. Pat. Appl. CA2173660 AA
(4) Inman et al. W09639401 A1
(5) Yanagisawa et al. W09638427
(6) Fujita et al., EP-745600 A1
(7) Ohara et al., W09626207 A1
(8) Ohara et al. W09611196 A1
(9) Malamas et al., U.S. Pat. No. 5,532,256 A
(10) Yanagisawa et al., EP-708098 A1
(11) Regnier et al., U.S. Pat. No. 5,478,853 A
(12) U.S. Pat. No. 5468762 A
(13) Ohara et al., W0952637 A1
(14) Antonucci et al. U.S. Pat. No. 5,457,109 A
(15) Yoshioka et al. JP07002852 A2
(16) Shibata et al., W09401433 A1
(17) Fujita et al., EP-543662 A2
(18) De Nanteuil et al., EP-559571 A1
(19) Zask et al., U.S. Pat. No. 5,236,941 A
(20) Ohnotaetal., W09214719
(21) Miyaoka et al., EP-489663 A1
(22) Arita et al., EP-506273 A2
(23) Hulin et al., J. Med. Chem. 35, 1853 (1992)
(24) Zask et al., J. Med. Chem. 33: 1418-1423 (1990)
(25) Clark U.S. Pat. No. 4,791,125A
(26) Iijima et al., EP-283035 A1
(27) Kees et al., U.S. Pat. No. 4,728,739 A
(28) Meguro et al., EP-177353 A2
(29) Hasler et al., EP-129747 A2
(30) Kawamatsu et al., EP-91761 A2
(31) Tontonez et al. Gene and Develop 8: 1224-1234 (1994)
(32) Tontonez et al. Cell 79: 1147-1156
(33) Lehmann et al., J. Biol. Chem. 270, 1-4, (1994)
(34) Amnri et al. J. Lipid Res. 32: 1449-1456 (1991)
(35) Grimaldi et al. Proc. Natl. Acad. Sci. USA 89: 10930 (1992)
(36) EP0745600
All references are incorporated by reference. While such disclosures constitute a large number of the insulin sensitizers, the instant invention is not so limited and can utilize any insulin sensitizer compound. The insulin sensitizers encompassed by the invention are compounds that improve insulin sensitivity as measured, for instance, by conducting standard assays such as those described in Examples H through M.
More preferred are the following insulin sensitizers: 
Especially preferred PPAR xcex3 agonists are Troglitazone, Pioglitiazone, ciglitazone, WAY-120,744, englitazone, AD 5075, SB219994, SB219993, BRL49653, GI-262570, darglitazone and analogs thereof.
Preferred RXR ligands are described in e.g. Heyman et al., W09710819 A1; Especially preferred RXR ligands are LG100268, LGD 1069, ALRT 1057 and analogs thereof
Other classes of insulin sensitizers are within the scope of the invention and include non-thiazolidinediones) such as SB 236636 and SB 219994, which are 3-aryl-2-alkoxy propanoic acids, PKC inhibitors, angiotensin II antagonists, and angiotensin converting enzyme inhibitors.
As expected from their mechanism of action, insulin-sensitizers are primarily effective in the hyperinsulinemic, early stages of type 2 diabetes. Efficacy is considerably reduced in advanced diabetes which is associated with severely disturbed beta-cell function and hence diminished insulin levels. This drug profile has been observed both in animal models of the disease as well as in the clinic. Hyperglycemia in young, hyperinsulinemic ZDF rats, for instance, is completely reversed by treatment with Troglitazone. Sreenan et al. Am. J. Physiol. 271: E742-747. ZDF rats in a more advanced, hypoinsulinemic phase of the disease, however, respond poorly to insulin sensitizer treatment. Brown et al. Diabetes 48: 1415-1424 (1999). In addition, hypoinsulinemic, streptozotocin induced diabetic mice do not respond to Troglitazone treatment. Fujiwara et al. Diabetes 37: 1549-1558 (1988). Clinical trials with Troglitazone have brought to light similarly variable responses in type 2 diabetics, with the non-response rate ranging from 35-62%. Valiquett T. et al. Diabetes 44 (Suppl.1): 406A (1995). In these trials it was found that the best predictor of efficacy was fasting insulin C peptide levels; the higher the C-peptide level, the greater the glucose-lowering effect in patients. Maggs DG et al. Ann. Intern. Med 128:176-185 (1998). Patients with sufficient pancreatic insulin secretory function thus respond well to therapy, whereas patients with decreased pancreatic function, characteristic of more advanced diabetes, respond poorly or are non-responders to therapy.
Insulin sensitizer treatment in general falls short of restoring euglycemia or normalizing HbA1c levels in atients. In clinical trials with Pioglitazone, for example, average blood glucose lowering and HbA1c reductions were xcx9c50 mg/dl and 0.6%, respectively. Mathisen et al. Diabetes 48 (Suppl.1): 441A (1998). In the patient populations treated, average reductions of  greater than 140 mg/dl and  greater than 3% would have been necessary to restore these parameters to normal values. A high rate of non-response and overall modest reductions in blood glucose levels have also been observed in clinical trials with Rosiglitazone. Patel et al. Diabetes, Obesity, and Metabolism 1: 165-172 (1999). There thus appears ample opportunity for agents such as the FBPase inhibitors to provide a benefit in combination with insulin sensitizers in the clinic.
FBPase inhibitors are likely to be efficacious both in early and advanced stages of type 2 diabetes. In animal studies they significantly lowered blood glucose in the hyperinsulinemic db/db mouse (a model of early type 2 diabetes, Examples S and T) as well as in a model of advanced type 2 diabetes: the insulinopenic streptozotocin-induced diabetic rat. In the ZDF rat, FBPase inhibitors were effective both in early diabetes (8-9 weeks of age, Examples N-R) as well as in advanced diabetes (16 weeks of age). Based on the pharmacological profile described above, the combination of FBPase inhibitors and insulin sensitizers will be effective across a broad patient population. In early stage diabetics, the insulin sensitizer and FBPase inhibitor are both likely to be fully effective, whereas in advanced diabetics, the response to insulin sensitizers may be partial whereas the FBPase inhibitor will maintain robust efficacy. The benefit of the combination in advanced diabetes will be a significant reduction in the number of non-responders to therapy (Example R). While the initial response of the combination may in large part be due to treatment with the FBPase inhibitor, blood glucose lowering may improve pancreatic function (Example P) and allow the insulin sensitizer to become more fully effective over time and in the long term provide enhanced glycemic control. In some cases, insulin sensitizers are best used in combination with agents that improve the actions of the insulin sensitizer, such as insulin, insulin analogs, RXR ligands, or insulin secretagogues (eg. the sulfonylureas). With the actions of the insulin sensitizer thus enhanced, combination treatment with an FBPase inhibitor will result in more effective glycemic control. Moreover, long term treatment will diminish the need for agents that enhance insulin levels.
FBPase inhibitors lower blood glucose both in the fasted (example T) and the fed state (examples N-S). This provides a broad opportunity for therapy in combination with insulin sensitizers. The combination could, for instance, be administered at mealtime and provide enhanced glycemic control over either agent alone by simultaneously enhancing glucose disposal and reducing the contribution of gluconeogenesis to hyperglycemia during the postprandial period. Meal time administration has the additional benefit of reducing the potential risk of hypoglycemia that could ensue from treatment with an FBPase inhibitor. Another possible dosing regimen may be the administation of the insulin sensitizer during the daytime, and administration of the FBPase inhibitor separately at bedtime. The insulin sensitizer will thus provide glycemic control by enhancing glucose disposal following daytime meals, whereas the FBPase inhibitor will control excessive glucose production by the liver known to occur to a greater extent during the overnight fast. There is precedent for the use of a hepatic glucose production suppressor during the overnight fast; insulin has been widely used in this application. Riddle, The Lancet 192-195 (1985).
An additional benefit of combination treatment is that it will allow a reduction in dose of both agents thereby reducing potential side effects. The most common side-effect of Troglitazone, for example, is hepatotoxicity which manifests itself as the elevation of liver enzymes (1% of patients). This side-effect has resulted in a recommendation for liver function monitoring every month for the first six months of treatment. In addition, an association between Troglitazone and increased heart weight in animals has led to recommendations that this drug be used cautiously in patients with congestive heart failure. Rosiglitazone treatment, although not reported to cause liver enzyme elevations, is known to significantly decrease haematocrit. All insulin sensitizers cause weight gain. As discussed above, in some cases efficacy with an insulin sensitizer can only be achieved with supplemental insulin or sulfonylurea administrations. Insulin has the undesirable side-effects of promoting weight gain, of exacerbating insulin resistance, and predisposing to hypoglycemia. Sulfonylureas also promote weight gain, increase the risk of hypoglycemia, and by overstimulating the pancreas can promote beta-cell degeneration. In certain animal models, FBPase inhibitors are known to elevate blood lactate and triglycerides and could therefore predispose to systemic acidosis and the vascular complication associated with hypertriglyceridemia. Combination treatment with an insulin sensitizer may suppress the potential lactate and triglyceride elevations associated with FBPase inhibitor treatment (Examples O and Q). Other side effects of FBPase inhibitors may manifest themselves in man. By treating patients with the combination of an insulin sensitizer and an FBPase inhibitor, the reduced dosages feasible are likely to significantly decrease the risks of the (potential) side-effects associated with the individual therapies.
While an insulin sensitizer-FBPase inhibitor combination is primarily envisaged for the treatment of type 2 diabetes and the associated renal, neuronal, retinal, micro- and macro-vascular and metabolic complications, treatment of other diseases that respond to improved glycemic control and improved insulin sensitivity is also possible. Patients with impaired glucose tolerance (IGT) are minimally hyperglycemic under ordinary circumstances but can become hyperglycemic following the ingestion of large glucose loads. IGT is a predictor of future diabetes and patients with this condition have become the target of diabetes prevention trials in recent years. Combination treatment of these patients, particularly at mealtime, restores a normal glucose response and reduces the risk of the development of diabetes. Another distinct group of subjects at high risk for the development of type 2 diabetes are women who suffer from polycystic ovary syndrome (POCS). Combination treatment is of benefit in these patients as well since they are typically, hyperinsulinemic, insulin resistant, and can suffer from IGT. Combination treatment is also useful for treating renal dysfunction and hypertension particularly in obese, insulin resistant, hyperinsulinemic patients with IGT. Other applications of combination treatment include gestational diabetes,.poorly controlled type 1 diabetes, obesity and dyslipidemia.
For the purposes of this invention, the compounds may be administered by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques.
Intraarterial and intravenous injection as used herein includes administration through catheters. Oral administration is generally preferred.
Pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating, and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
The pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.
Compounds of the invention may be administered as a daily dose or an appropriate fraction of the daily dose (e.g. bid). Administration of the FBPase inhibitor may occur at or near the time in which the insulin sensitizer active ingredient is administered or at a different time. Simultaneous administration of the active ingredients is achieved either by administration of the active ingredients in the same or different formulations. Formulations include time-release formulations intended to release either both of the active ingredients simultaneously or to stage the release of the active ingredients such that release, absorption and systemic exposure occurs with one of the ingredients before the other.
The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may contain 20 to 2000 xcexcmol (approximately 10 to 1000 mg) of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions.
As noted above, formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or nonaqueous liquid; or as an oil-in-water liquid emulsion or a water in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent. Molded tablets may be made by molding in a""suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Formulations suitable for parenteral administration include aqueous and on-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, a fructose-1,6-bisphosphatase inhibitor compound and an insulin sensitizer.
It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those skilled in the art.
Capsules comprising FBPase inhibitors suitable for oral administration according to the methods of the present invention may be prepared as follows: (1) for a 10,000 capsule preparation: up to 5000 g of FBPase inhibitor is blended with other ingredients (as described above) and filled into capsules which are suitable for administration depending on dose, from about 1 capsules per day to about 8 capsules per day (2 capsules per 6 hours), to an adult human.
Capsules comprising insulin sensitizers suitable for oral administration according to the methods of the present invention may be prepared as follows: (1) for a 10,000 capsule preparation: up to 5000 g of insulin sensitizer is blended with other ingredients (as described above) and filled into capsules which are suitable for administration depending on dose, from about 1 capsules per day to about 8 capsules per day (2 capsules per 6 hours), to an adult human.
Capsules comprising FBPase inhibitors and insulin sensitizers suitable for oral administration according to the methods of the present invention may be prepared as follows: (1) for a 10,000 capsule preparation: up to 2500 g of FBPase inhibitor and up to 2500 g of insulin sensitizer are blended with other ingredients (as described above) and filled into capsules which are suitable for administration depending on dose, from about 1 capsules per day to about 8 capsules per day (2 capsules per 6 hours), to an adult human.